Hsp22对SCA3/MJD转基因果蝇模型的保护作用研究
摘要
遗传性脊髓小脑型共济失调(Spinocerebellar ataxia，SCAs)是一类常见的神经系统退行性疾病，多呈常染色体显性遗传，临床主要表现为共济失调、构音障碍、吞咽困难、眼球震颤、运动障碍等，致残率、致死率高。SCAs具有明显的遗传异质性，目前已经克隆的和已定位尚未克隆的致病基因至少已有三十余种。对不同地域、人种的研究发现尤以SCA3／MJD(Machado-Joseph disease，MJD)亚型最为常见，在中国人群中，该型几乎占所有遗传性脊髓小脑型共济失调病人的50％。SCA3／MJD致病基因MJD1编码区的3′端含一段CAG三核苷酸重复序列，正常个体其MJD1基因的CAG三核苷酸重复约12-40次，而SCA3／MJD患者其MJD1基因的CAG三核苷酸重复次数扩展到55-84次，且重复次数越多，发病年龄越早，症状越严重。包括SCA3／MJD在内，目前至少有9种神经退行性疾病都是由于疾病蛋白内多聚谷氨酰胺(polyglutamine，polyQ)肽链异常扩增所致，在病理、发病机制以及临床表现上均有相当程度的相似性，即含有异常扩展的polyQ肽链的蛋白在神经系统特定区域(小脑、脑干、脊髓等)导致神经元变性死亡，并形成核内包涵体(neuronal intranuclear inclusions，NIIs)。虽然目前的研究已经明确异常扩展的polyQ突变蛋白促发了整个病变过程，但引起神经元损害的具体机制还不清楚。可能的机制包括基因突变后产生的polyQ片断错误折叠形成的聚集物，影响了蛋白一蛋白相互作用，改变了蛋白功能，干扰了基本的细胞过程如转录，蛋白降解，氧化应激以及生存／凋亡通路等。对包括SCA3／MJD疾病在内的一些polyQ疾病的标志性的病理结构—神经元核内包涵体的免疫反应研究发现，在polyQ疾病患者脑内以及细胞和转基因动物模型中，大量的热休克蛋白被募集进入NIIs，提示细胞内有助于蛋白折叠，聚合物解聚和扩增的poly(Q)降解的机制被激活。国外研究也已经证实大分子热休克蛋白如Hsp70，Hsp40对SCA3／MJD疾病动物模型具有明显的保护作用。Hsp22属一种小分子热休克蛋白(small Heat Shock protein，sHsp)家族成员，同样具有分子伴侣活性，在通过促进蛋白折叠恢复蛋白正常生理结构和功能，以及转运，抗氧化应激和抗调亡等方面发挥重要作用。我们在前期研究中还发现人Hsp22基因突变还导致了另外一种神经系统遗传病—腓骨肌萎缩症，突变蛋白形成了特征性的蛋白聚集物，也说明Hsp22在维持蛋白正常生理结构和功能中具有重要作用。Hsp22还是一种线粒体蛋白，线粒体对活性氧簇非常敏感，提高Hsp22的表达水平有助于保护线粒体蛋白防御氧化应激。而在polyQ疾病中氧化应激是一种较为常见的发病机制，对该类疾病动物模型进行抗氧化处理，疾病表型得到了显著改善。鉴于Hsp22的上述作用，我们设想若能利用Hsp22对polyQ蛋白进行干预，或许能改善异常扩增的polyQ蛋白的错误折叠，抑制polyQ蛋白的细胞毒性，有助于治疗包括SCA3／MJD在内的polyQ疾病。作为一种经典的模式生物，转基因果蝇模型在神经退行性病和遗传病的研究中发挥了日益重要的作用，目前国外已经构建了包括SCA3／MJD疾病在内的许多神经系统退行性疾病和遗传病转基因果蝇模型。在本实验中，我们选用gmr-GAL4和elav-GAL4，利用经典的GAL4-UAS系统，将含有78个CAG重复扩增的ataxin-3蛋白片断(MJDtr-Q78)分别在果蝇眼睛和神经系统选择性表达，结果MJDtr-Q78在果蝇眼睛的表达导致果蝇眼睛视网膜细胞严重变性坏死，眼睛结构几乎完全破坏，而在果蝇神经系统的强烈表达则导致了果蝇的发育明显受阻，所有果蝇完全致死，从而成功地构建了gmr-GAL4／UAS和elav-GAL4／UAS系统SCA3／MJD转基因果蝇模型。然后我们通过果蝇杂交将与人类Hsp22具有相似生物学特点的果蝇内源性Hsp22在果蝇眼睛和神经系统过表达，并利用遗传方法和热休克反应使Hsp22以不同水平表达，结果发现Hsp22过表达显著抑制了MJDtr-Q78的毒性，果蝇眼睛视网膜变性、坏死明显缓解，果蝇存活能力大幅度提高，神经元核内包涵体的数量也明显减少；Hsp22对MJDtr-Q78的毒性抑制作用与神经元核内包涵体的减少程度以及Hsp22的表达水平相关，从而证实了Hsp22对SCA3／MJD疾病具有保护作用。Hsp22对SCA3／MJD转基因果蝇模型的保护作用提示增强某些热休克蛋白等分子伴侣活性对包括polyQ疾病在内的神经退行性疾病和遗传病或许是一种潜在的治疗方法，同时转基因果蝇模型的使用有助于更好的理解神经退行性疾病和遗传病的发病机制。
The hereditary spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive in coordination of gait and often associated with poor coordination of hands, speech, and eye movements, most of them are inherited in an autosomal dominant manner, and lead to the early death and disability of patients involved. To date, at least 30 genes responsible for SCAs have been cloned or located to their distinct regions on certain chromosome but still waited to be cloned. Spinocerebellar ataxia type 3, also known as Machado Joseph disease (SCA3/MJD), is the most common genotype of SCAs in world wide and account almost for 50% in Chinese SCAs patients. Besides SCA3/MJD, at least 9 human neurodegenerative diseases known as polyQ diseases show considerable similarity in pathology, pathgenesis, and clinical manifestations because they share a common molecular mechanism involving expansion of a polyglutamine tract (polyQ) within their respective disease-causing proteins, and expanded polyQ confers a toxic gain-of-function property on the otherwise unrelated disease proteins, leading to neuronal dysfunctions, cell loss and the form of Neuronal intranuclear inclusions in specific areas (spinal cord, cerebella, brain stem, et al. ). In SCA3/MJD, the glutamine repeat, which is located near the carboxyl terminus of the protein, normally contains 12-40 repeats and becomes expanded to 55-84 repeats pathologically. The longer the repeat, the earlier the onset and the more severe the disease.
The mechanism of SCA3/MJD is still not fully understood, as were known. In particular, abnormal protein conformation(s) promoted by polyQ expansion seems to be the key to pathogenesis in SCA3/MJD and other polyQ diseases. This toxicity is linked to protein misfolding and oligomerization of the mutant protein alters interactions of the mutant protein with its normal interacting partners, leads to dysfunction of proteins, and interferes with the basic cell process such as gene transcription, degrade of protein, oxidative stress and survival/apoptotic pathway. Moreover, expanded polyglutamine proteins form aggregates, including neuronal intranuclear inclusions (NIIs), a common pathologic hallmarker of disease, possibly due to misfolding of proteins. Histology and Immunocytochemistry studies show the neuronal intranuclear inclusions (NIIs) often contain other misfolding proteins, components of the proteasome system, and molecular chaperones. The presence of chaperones in NIIs raises the possibility that chaperones may contribute to pathology in situations. It is suggested that disease pathogenesis may include activation of cellular stress pathways to help refold, disaggregate or degrade the mutant disease proteins. Some studies indicated that over expression of specific chaperone proteins Hsp70 and Hsp40 suppressed neurodegeneration induced by polyQ in transfected cells and Drosophila models. As one of chaperone proteins, small molecular heat shock protein Hsp22 plays important roles in maintaining cellular functions during aging, promoting protein renaturation through protein folding, and inhibiting cytochrome C-mediated activation of casepases and protect cell against apoptosis. Because oxidative damage is often observed in polyQ disease and mitochondria are sensitive to reactive oxygen species, Hsp22 is a protein localized in mitochondria, the increased level of Hsp22 could protect mitochondria protein. In our previous work, the mutation of Hsp22 gene causes Charcot-Marie-Tooth disease, another kind of neurodegenerative disease. It is also suggested that Hsp22 may contribute to the normal structure and function of protein. Therefore, we have enough reason to make a hypothesis that over-expression of Hsp22 may reduce polyQ toxicity, and suppress neurodegeneration caused by the mutant ataxin-3.
As a classic animal model, transgenic drosophila play an important role in research of neurodegenerative and neurogenetic disorders. To date, many transgenic drosophila models were set up for neurodegenerative and neurogenetic disorders including SCA3/MJD.
We expressed a truncated version of the human expanded ataxin-3 protein (MJDtr-Q78) in both the neural system and eyes using the GAL4-UAS transformation system. This system allows targeted gene expression when transgenic flies bearing a UAS transgene are crossed with fly lines that express GAL4 in tissue-specific patterns. We used the gene promoter gmr-GAL4 and elav-GAL4, which drive expression in all cells of the developing eye and neuron, respectively. Expression of MJDtr-Q78 had severe effects on morphology and pigmentation of the eye, led to the death of all Drosophila lavas for defected development and neuronal intranuclear inclusions (NIIs) formation. Then, we over expressed the Hsp22 in flies, and found that over expression of endogen Drosophila Hsp22 can notably suppress the toxicity of MJDtr-Q78, and the level of Hsp22 expression was in consistent with rehabilitation for degeneratives of drosophila eyes, drosophila lifespan and the number of nuclear inclusion. It is confirmed that expression of Hsp22 protects the SCA3/MJD from neurodegeneration on model animal.
These studies indicate that manipulating specific molecular chaperones including Hsp22 may provide a means of treating neurodegenerative diseases including polyQ disease associated with abnormal protein conformation and toxicity. In these ways, the transgenic drosophila models could help us to further understand the pathogenesis of neurodegenerative diseases including polyQ disease.
The hereditary spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive in coordination of gait and often associated with poor coordination of hands, speech, and eye movements, most of them are inherited in an autosomal dominant manner, and lead to the early death and disability of patients involved. To date, at least 30 genes responsible for SCAs have been cloned or located to their distinct regions on certain chromosome but still waited to be cloned. Spinocerebellar ataxia type 3, also known as Machado Joseph disease (SCA3/MJD), is the most common genotype of SCAs in world wide and account almost for 50% in Chinese SCAs patients. Besides SCA3/MJD, at least 9 human neurodegenerative diseases known as polyQ diseases show considerable similarity in pathology, pathgenesis, and clinical manifestations because they share a common molecular mechanism involving expansion of a polyglutamine tract (polyQ) within their respective disease-causing proteins, and expanded polyQ confers a toxic gain-of-function property on the otherwise unrelated disease proteins, leading to neuronal dysfunctions, cell loss and the form of Neuronal intranuclear inclusions in specific areas (spinal cord, cerebella, brain stem, et al. ). In SCA3/MJD, the glutamine repeat, which is located near the carboxyl terminus of the protein, normally contains 12-40 repeats and becomes expanded to 55-84 repeats pathologically. The longer the repeat, the earlier the onset and the more severe the disease.
The mechanism of SCA3/MJD is still not fully understood, as were known. In particular, abnormal protein conformation(s) promoted by polyQ expansion seems to be the key to pathogenesis in SCA3/MJD and other polyQ diseases. This toxicity is linked to protein misfolding and oligomerization of the mutant protein alters interactions of the mutant protein with its normal interacting partners, leads to dysfunction of proteins, and interferes with the basic cell process such as gene transcription, degrade of protein, oxidative stress and survival/apoptotic pathway. Moreover, expanded polyglutamine proteins form aggregates, including neuronal intranuclear inclusions (NIIs), a common pathologic hallmarker of disease, possibly due to misfolding of proteins. Histology and Immunocytochemistry studies show the neuronal intranuclear inclusions (NIIs) often contain other misfolding proteins, components of the proteasome system, and molecular chaperones. The presence of chaperones in NIIs raises the possibility that chaperones may contribute to pathology in situations. It is suggested that disease pathogenesis may include activation of cellular stress pathways to help refold, disaggregate or degrade the mutant disease proteins. Some studies indicated that over expression of specific chaperone proteins Hsp70 and Hsp40 suppressed neurodegeneration induced by polyQ in transfected cells and Drosophila models. As one of chaperone proteins, small molecular heat shock protein Hsp22 plays important roles in maintaining cellular functions during aging, promoting protein renaturation through protein folding, and inhibiting cytochrome C-mediated activation of casepases and protect cell against apoptosis. Because oxidative damage is often observed in polyQ disease and mitochondria are sensitive to reactive oxygen species, Hsp22 is a protein localized in mitochondria, the increased level of Hsp22 could protect mitochondria protein. In our previous work, the mutation of Hsp22 gene causes Charcot-Marie-Tooth disease, another kind of neurodegenerative disease. It is also suggested that Hsp22 may contribute to the normal structure and function of protein. Therefore, we have enough reason to make a hypothesis that over-expression of Hsp22 may reduce polyQ toxicity, and suppress neurodegeneration caused by the mutant ataxin-3.
As a classic animal model, transgenic drosophila play an important role in research of neurodegenerative and neurogenetic disorders. To date, many transgenic drosophila models were set up for neurodegenerative and neurogenetic disorders including SCA3/MJD.
We expressed a truncated version of the human expanded ataxin-3 protein (MJDtr-Q78) in both the neural system and eyes using the GAL4-UAS transformation system. This system allows targeted gene expression when transgenic flies bearing a UAS transgene are crossed with fly lines that express GAL4 in tissue-specific patterns. We used the gene promoter gmr-GAL4 and elav-GAL4, which drive expression in all cells of the developing eye and neuron, respectively. Expression of MJDtr-Q78 had severe effects on morphology and pigmentation of the eye, led to the death of all Drosophila lavas for defected development and neuronal intranuclear inclusions (NIIs) formation. Then, we over expressed the Hsp22 in flies, and found that over expression of endogen Drosophila Hsp22 can notably suppress the toxicity of MJDtr-Q78, and the level of Hsp22 expression was in consistent with rehabilitation for degeneratives of drosophila eyes, drosophila lifespan and the number of nuclear inclusion. It is confirmed that expression of Hsp22 protects the SCA3/MJD from neurodegeneration on model animal.
These studies indicate that manipulating specific molecular chaperones including Hsp22 may provide a means of treating neurodegenerative diseases including polyQ disease associated with abnormal protein conformation and toxicity. In these ways, the transgenic drosophila models could help us to further understand the pathogenesis of neurodegenerative diseases including polyQ disease.
引文
[1] Ella Bossy-Wetzel, Robert Schwarzenbacher etc. Molecular pathways to neurodegeneration Nat Med, 2004, July: S2-S9
[2] Serge Przedborski, Miquel Vila etc. Neurodegeneration: What is it and where are we J Clin Invest. 2003,111(1): 3-10
[3] Lars Bertram, Rudolph E.The genetic epidemiology of neurodegenerative disease TanziJ Clin Invest, 2005,115(6): 1449-57
[4] Mayeux R.Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003 ;26: 81-104. Epub 2003 Jan 24.
[5] Mark P. Mattson. Pathways towards and away from Alzheimer's disease Nature.2004,430(5): 631-9
[6] Edward H Koo, Raphael Kopan. Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration Nat Med.2004, July: S26-S33
[7] T. Tsuji, A. Shiozaki, etc Proteomic Profiling and Neurodegeneration in Alzheimer's disease Neurochem Res, 2002,27(10): 1245-53
[8] Michael Paul Murphy etc.Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production Nat Med, 2005, 11(5): 545-50
[9] Miquel Vila, Serge Przedborski. Genetic clues to the pathogenesis of Parkinson's disease Nat Med, 2004, July: S58-S62
[10] Ted M. Dawson, Valina L. Dawsonl. Molecular Pathways of Neurodegeneration in Parkinson's disease Science.2003,302: 917-22
[11] Yuzuru Imai, Ryosuke Takahashi.How do Parkin mutations result in neurodegeneration Curr Opin Neurobiol, 2004,14:384-389?
[12] Zhizhong Dong, Boris Ferger. Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-l.PNAS, 2003, 100(21):12438-12443.
[13] Seppi K, Yekhlef F, Diem A, et al. Progression of parkinsonism in multiple s ystem atrophy. J Neurol 2005; 252:91-6.
[14] Vanacore N, Bonifati V, Fabbrini G, et al. Case-control study of multiple system atrophy. Mov Disord 2005; 20:158-63.
[15] Watanabe H, Saito Y, Terao S, et al. Progression and prognosis in multiple system atrophy: An analysis of 230 Japanese patients. Brain 2002,125:1070-1083.
[16] Shaw PJ. Molecular and cellular pathways of neurodegeneration in motor neurone disease. J Neurol Neurosurg Psychiatry. 2005 Aug;76(8): 1046-57.
[17] The molecular genetics of non-ALS motor neuron diseases. Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):986-1000.
[18] S. Maekawa, S. Al-Sarraj, M. Kibble. Cortical selective vulnerability in motor neuron disease: a morphometric study Brain, Jun 2004; 127: 1237 -1251.
[19] Orr HT, Chung MY, Banfi S, et al. Expansion of an unstable trinucleotide CAGrepeats in spinocerebellar ataxia type 1. Nat Genet, 1993,4(3):221-226.
[20] Pulst SM, Nechiporuk A, Nechiporuk T, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type2 .Nat Genet 1996,14(3): 269-276.
[21] [21] Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet, 1994, 8(3): 221-228.
[22] Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet, 1997,15(1): 62-69.
[23] Lindblad K, Savontaus ML, Stevanin G, et al. An expanded CAG repeat sequence in spinocerebellar ataxia type 7. Genome Res, 1996,6(10): 965-971.
[24] Nakamura K, Jeong SY, Uchihara T, et al. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet, 2001,10(14): 1441-1448.
[25] Jana NR, Nukina N. Recent advances in understanding the pathogenesis of poly glutamine diseases: involvement of molecular chaperones and ubiquitin-proteasome pathway. J Chem Neuroanat, 2003,26(2):95-101.
[26] Amato.A,Prior.T,W.Barohn, Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology, 1993,43: 791-794,
[27] Andrew S. E, Goldberg Y. PThe relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nature Genet, 1993, 4: 398 -403.
[28] Koide R, Ikeuchi T, Onodera O. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet, 1994, 6:9-13,
[29] Andrew S. E, Goldberg Y. P The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nature Genet, 1993, 4: 398 -403,
[30] Kazemi-Esfarjani, P. and Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science, 2000,287,1837-1840.
[31] Jill Heemskerk, Allan J. etc From chemical to drug: neurodegeneration drug screening and the ethics clinical trials Jill Heemskerk, Allan J. etc.Nat neurosci suppl, 2002, 5: 1027-9.
[32] Haibin Xia, Qinwen Mao etc RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia.Nat Med. 2004, 10(8): 816-20.
[33] Olle Lindvall, Zaal Kokaia etc. Stem cell therapy for human neurodegenerative disorders-how to make it work Nat Med.2004, July: S42-S50.
[34] Matthias Rothermundt, Marion Peters etc S100B in Brain Damage and Neurodegeneration Microsc Res Tech. 2003, 60:614-32 .
[35] Leo H.Wang, Cagri G. MIXED-LINEAGE KINASES: A Target for the Prevention of Neurodegeneration Annu Rev Pharmacol Toxicol., 2004, 44: 451-74.
[36] Amato.A, Prior.T, W.Barohn, Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology, 1993, 43: 791-794,
[37] Michalik A, Van Broeckhoven C. Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet, 2003, 12,Spec No 2:R173-186.
[38] Bates G. Huntingtin aggregation and toxicity in Huntington's disease. Lancet, 2003,361(9369): 1642-1644.
[39] Arrasate M, Mitra S, Schweitzer ES, et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature, 2004, 431(7010): 805-810.
[40] Cowan KJ, Diamond MI, Welch WJ. Polyglutamine protein aggregation and toxicity are linked to the cellular stress response. Hum Mol Genet, 2003, 12(12): 1377-1391.
[41] Lee WC, Yoshihara M, Littleton JT. Cytoplasmic aggregates trap polyglu-tamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease. Proc Natl Acad Sci U S A, 2004,101(9): 3224-3229.
[42] Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease Nat Med, 2004,10 Suppl: S10-7.
[43] Jiang H, Tang BS, Xu B, Zhao GH, Shen L, Tang JG, Li QH, Xia K.Frequency analysis of autosomal dominant spinocerebellar ataxias in mainland Chinese patients and clinical and molecular characterization of spinocerebellar ataxia type 6.Chin Med J (Engl). 2005 May 20; 118(10):837-43.
[44] Jiang M, Jin CL, Lin CK, Qiu GR, Liu ZL, Wang CX, Sun KL.Analysis and application of SCA1 and SCA3/MJD gene CAG repeats in Han population in Northeastern China Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2004 Feb; 21(1):83-5.
[45] Matsumura R, Futamura N, Ando N, Ueno S.Frequency of spinocerebellar ataxia mutations in the Kinki district of Japan. Acta Neurol Scand. 2003 Jan; 107(l):38-41.
[46] Basu P, Chattopadhyay B, Gangopadhaya PK, Mukherjee SC, Sinha KK, Das SK, Roychoudhury S, Majumder PP, Bhattacharyya NP.Analysis of CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci in spinocerebellar ataxia patients and distribution of CAG repeats at the SCA1, SCA2 and SCA6 loci in nine ethnic populations of eastern India.Hum Genet. 2000 Jun;106(6):597-604.
[47] Tang BS, Liu C, Shen L, et al. Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. Arch Neurol 2000; 57:540-544.
[48] Shimizu Y, Yoshida K, Okano T, Ohara S, Hashimoto T, Fukushima Y, Ikeda S.Regional features of autosomal-dominant cerebellar ataxia in Nagano: clinical and molecular genetic analysis of 86 families. J Hum Genet. 2004;49(11):610-6. Epub 2004 Oct 8.
[49] Kubis N, Durr A, Gugenheim M, Chneiweiss H, Mazzetti P, Briee A, Bouche P.Polyneuropathy in autosomal dominant cerebellar ataxias: phenotype- genotype correlation.Muscle Nerve. 1999 Jun;22(6):712
[50] Chowdary TK, Raman B, Ramakrishna T, et al.Mammalian Hsp22 is a heat -inducible small heat-shock protein with chaperone-like activity. Biochem J, 2004, 381 (Pt 2): 379-387
[51] Gober MD, Depre C, Aurelian L. Correspondence regarding M. V. Kim et al. "Some properties of human small heat shock protein Hsp22 (H11 or HspB8)". Biochem Biophys Res Commun, 2004, 321(2): 267-268.
[52] Tao D, Lu J, Sun H, et al. Trichostatin A extends the lifespan of Drosophila melanogaster by elevating Hsp22 expression Acta Biochimica et Biophysia Sinica, 2004, 36: 618-622.
[53] Sun X, Fontaine JM, Rest JS, et al. Interaction of human HSP22 (HSPB8) with other small heat shock proteins. J Biol Chem. 2004,279(4): 2394-2402.
[54] Kurapati Passananti H B, Rose M R, et al. Increased Hsp22 RNA levels in Drosophila lines genetically selected for increased longevity Gerontol. A Biol.Sci. Med. Sci., 2000, 55: 552-559.
[55] Morrow G, Samson M, Michaud S, et al. Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress.The FASEB J, 2004,18:598-599.
[56] King V, Tower J. Aging-specific expression of Drosophila Hsp22. Devel Biol. 1999,207: 107-118.
[57] Rubin G M, Lewis E B. A brief history of Drosophila's contributions to genome research. Science, 2000,287(5461):2216-2218
[58] St Johnston D. The art and design of genetic screens: Drosophila melanogaster. Nat Rev Genet, 2002, 3(3): 176-188
[59] Winkelmann BR, Hager J A Systematic Analysis of Human Disease-Associated Gene Sequences In Drosophila melanogasterGenome Res. 2001 June; 11(6): 1114-1125.
[60] O'Kane CJ.Modelling human diseases in Drosophila and Caenorhabditis Semin Cell Dev Biol. 2003 Feb;14(1):3-10
[61] Lengyel J A, Iwaki D D. It takes guts: the Drosophila hind-gut as a model system for organogenesis. Dev Biol, 2002,243(1): 1-19
[62] Buchanan, R.L. and Benzer, S. Defective glia in the Drosophila brain degeneration mutant drop-dead. Neuron, 1993, 10, 839-850 .
[63] Kretzschmar, D., Hasan, G., Sharma, S., Heisenberg, M., and Benzer, S. The swiss cheese mutant causes glial hyperwrapping and brain degeneration in Drosophila. J. Neurosci. 1997,17,7425-7432
[64] Palladino, M.J., Bower, J.E., Kreber, R., and Ganetzky, B. Neural dysfunction and neurodegeneration in Drosophila Na+/K+ ATPase alpha subunit mutants. J. Neurosci. 2003,23,1276-1286
[65] Trotta, N., Orso, G., Rossetto, M.G., Daga, A., and Broadie, K. The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function. Curr. Biol. 2004, 14,1135-1147.
[66] Jackson, G.R., Salecker, I., Dong, X., Yao, X., Arnheim, N., Faber, P.W., MacDonald, M.E. and Zipursky, S.L. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron, 1998,21, 633-642
[67] Terrence F. Satterfield, Stephen A .Drosophila Homolog of the Polyglutamine Disease Gene SCA2 Is a Dosage-Sensitive Regulator of Actin Filament Formation Genetics, Vol. 162,1687-1702, December 2002, Copyright (?) 2002
[68] Morwena Latouche, Christelle Lasbleiz, Elodie Martin,A Conditional Pan-Neu ronal Drosophila Model of Spinocerebellar Ataxia 7 with a Reversible Adult Phenotype Suitable for Identifying Modifier Genes J. Neurosci., Mar 2007,27: 2483 - 2492.
[69] Warrick JM, Paulson HL, Gray-Board GL Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila Cell. 1998 Jun 12; 93(6):939-49.
[70] Brand, A.H., Perrimon, N., 1993. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development, 118(2):401-415.
[71] Serggio Lanata. Head Involution Defective (hid) Iap Antagonist - A Possible Transcriptional Gene Target for Tumor Suppressor Gene p53 Journal of Undergraduate Research, 2003,435: 156-178.
[72] Fernandez-Funez P, Nino-Rosales M L, de Gouyon B, et al. identifycation of genes that modify ataxin-1 -induced neurodegenera tion. Nature, 2000, 408: 101-106.
[73] Feany, M.B. and Bender, W.W. A Drosophila model of Parkinson's disease. Nature 2000, 404,394-398.
[74] Takeyama, K, Ito, S, Yamamoto, A, Tanimoto, H, Furutani, T, Kanuka, H, Miura, M., Tabata, T. and Kato, S. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron, 2002,35, 855-864.
[75] Phelps CB, Brand AH. Ectopic gene expression in Drosophila using GAL4system. Methods, 1998, 14(4): 367-379
[76] Wilder E. Ectopic expression in Drosophila. Methods Mol Biol., 2000, 137: 9-14.
[77] Lin, D.M. and Goodman, C.S., 1994. Ectopic and increased expression of Fasciclin Ⅱ alters motoneuron growth cone guidance. Neuron 13, pp. 507-523.
[78] Fortini M E, Bonini N M. Modeling human neurodegenenrative diseases in Drosophila. Trends in Genetics, 2000, 16 (4): 161-167.
[79] Paul Mark B. Medina, Lance L. SwickA Novel Forward Genetic Screen for Identifying Mutations Affecting Larval Neuronal Dendrite Development in Drosophila melanogaster Genetics. 2006 April; 172(4): 2325-2335
[80] Knud Nairz, Peder Zipperlen, Charles Dearolf. A reverse genetic screen in Drosophila using a deletion-inducing mutagen Genome Biol. 2004; 5(10): R83.
[81] Yong Q. Zhang David B. Friedman Zhe Wang Protein Expression Profiling of the Drosophila Fragile X Mutant Brain Reveals Up-regulation of Monoamine Synthesis Mol. Cell. Proteomics 4: 278-290, 2005.
[82] Muller H.j. Genetic variability, twin hybrids and constant hybrids, in. a case of balanced lethal factors. Genetics 1918; 3: 422-499
[83] Koshy, B.T. and Zoghbi, H.Y. The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis. Brain Pathol, 1997, 7: 927-942.
[84] Paulson, H.L. Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis) fold. Am. J. Hum. Genet. 1999, 64: 339-345.
[85] http://flybase.org.
[86] Durr A, Stevanin G, Cancel G. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular and neuropathologic features. Ann. Neurol., 1996, 39: 490-499.
[87] Joonil Jung and Nancy Bonini CREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease. Science, 2007, 315: 1857-1859.
[88] Bernd O. Evert, Julieta Araujo, Ana M. Ataxin-3 Represses Transcription via Chromatin Binding, Interaction with Histone Deacetylase 3, and Histone Deacetylation. J. Neurosci., 2006, 26: 11474 - 11486.
[89] Brigit E. Riley and Harry T Orr. Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle. Genes & Dev, 2006, 20: 2183-2192.
[90] Norma M. Wills and John F. Atkins The potential role of ribosomal frameshifting in generating aberrant proteins implicated in neurodegenerative diseases.RNA, 2006,12: 1149 -1153.
[91] Gretta Abou-Sleymane, Frederic Chalmel, Dominique Helmlinger et al. Polyglutamine expansion causes neurodegeneration by altering the neuronal differentiation program.Hum. Mol. Genet, Mar 2006,15: 691 - 703.
[92] Annette Haacke, Sarah A. Broadley, Raina Boteva, et al.Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3.Hum. Mol. Genet, 2006,15: 555 - 568.
[93] S Tabrizi. Neurodegenerative diseases neurobiology pathogenesis and therapeutics. J. Neurol. Neurosurg. Psychiatry, 2006,77: 284.
[94] Kezhong Zhang and Randal J. Kaufman .The unfolded protein response: A stress signaling pathway critical for health and disease. Neurology, Jan 2006; 66:S102-S109
[95] Stephen C . Meredith .Protein Denaturation and Aggregation: Cellular Responses to Denatured and Aggregated Proteins. Ann. N.Y. Acad. Sci., 2005,1066:181-221.
[96] Aaron B. Bowman, Seung-Yun Yoo, Nico P. Dantuma, et al. Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation.Hum. Mol. Genet, 2005,14: 679 - 691.
[97] Daniel Goti, Scott M. Katzen, Jesse Mez, et al. A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical ConcentrationJ. Neurosci, 2004,24:10266-10279
[98] Yeon-jeong Kim .Role of Polyunsaturated Fatty Acids for Misfolding Protein Aggregations: Implication for Neurodegenerative Diseases.Ann. N.Y. Acad. Sci., 2006; 1086: 11-20
[99] Tapan K Chaudhuri and Subhankar. Paul.Protein-misfolding diseases and chaperone-based therapeutic approaches. FEBS J. 2006,273: 1331 - 1349
[100] Jasna Brujic, Rodolfo I. Z. Hermans, et al.Dwell-Time Distribution Analysis of Polyprotein Unfolding Using Force-Clamp Spectroscopy.Biophys. J. 2007, 92: 2896 - 2903.
[101] Michelle K. M. Chow, Andrew M. Ellisdon,et al.Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability: IMPLICATIONS FOR MISFOLDING AND DISEASE. J. Biol. Chem.2004,279: 47643 - 47651.
[102] Valerie Askanas and W. King Engel. Inclusion-body myositis: A myodegen erative conformational disorder associated with Aβ, protein misfolding, and proteasome inhibition. Neurology, 2006; 66: S39 - S48.
[103] Barnaby C.H. May, Cedric Govaerts, Fred E.Cohen Developing therapeutics for the diseases of protein misfolding. Neurology, 2006, 66: S118 - S122 Hum. Mol. Genet. 2003,12: 3195 - 3205.
[104] Arjan Quist, Ivo Doudevski, Hai Lin, Rushana Azimova,et al.Amyloid ion channels: A common structural link for protein-misfolding disease .PNAS, 2005,102: 10427-10432
[105] Hilal A. Lashuel.Membrane Permeabilization: A Common Mechanism in Protein-Misfolding Diseases. Sci, Aging, Knowl. Environ. 2005; 2005: pe28.
[106] Ian V. J. Murray, Liu Liu, Hiroaki Komatsu,et al. Membrane-mediated Amyloidogenesis and the Promotion of Oxidative Lipid Damage by Amyloid βProteins.J. Biol. Chem., Mar 2007; 282: 9335 - 9345.
[107] Stephanie L. H. Miller, Erica L. Scappini.Ubiquitin-interacting Motifs Inhibit Aggregation of PolyQ-expanded Huntingtin J. Biol. Chem. 2007,282: 10096 - 10103.
[108] Jana NR, Nukina N. Recent advances in understanding the pathogenesis of poly glutamine diseases: involvement of molecular chaperones and ubiquitin protea- some pathway. J Chem Neuroanat, 2003,26(2):95-101.
[109] Tapan K Chaudhuri and Subhankar Paul Protein-misfolding diseases and chaperone-based therapeutic approaches .FEBS J. 2006,273: 1331 -1349.
[110] Yaohui Chai, Stacia L. Koppenhafer, Nancy M. Bonini,et al. Analysis of the Role of Heat Shock Protein (Hsp) Molecular Chaperones in Polyglutamine Disease.J.Neurosci. 1999; 19: 10338.
[111] Hideki Sakahira, Peter Breuer, Manajit K. Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. PNAS, 2002,99: 16412.
[112] Konstanze F. Winklhofer, Iris H. Henn, Penelope C ,et al.Inactivation of Parkin by Oxidative Stress and C-terminal Truncations: A PROTECTIVE ROLE OF MOLECULAR CHAPERONES. J. Biol. Chem, 2003, 278: 47199 - 47208.
[113] H.Y. Edwin Chan, John M. Warrick, Gladys L,et al..Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila.Hum. Mol. Genet., 2000, 9: 2811 - 2820.
[114] Hiroaki Adachi, Masahisa Katsuno, Makoto Minamiyama,et al.Heat Shock Protein 70 Chaperone Overexpression Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model by Reducing Nuclear-Localized Mutant Androgen Receptor Protein.J. Neurosci. 2003; 23: 2203.
[115] Paul J. Muchowski, Gregor Schaffar, Annie Sittler,et al.Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils.PNAS, 2000; 97: 7841.
[116] David F. Smith, Luke Whitesell, and Emmanuel Katsanis Molecular Chaperones: Biology and Prospects for Pharmacological Intervention. Pharmacol. 1998; 50: 493
[117] Serena Carra, Mitchel Sivilotti, Aura T. Chavez Zobel .HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells.Hum. Mol. Genet,2005,14: 1659 - 1669
[118] Yu Sun, Thomas H. MacRae. The small heat shock proteins and their role in human disease.FEBS J. 2005,272: 2613 - 2627.
[119] David G. Nicholls and Samantha L. Budd Mitochondria and Neuronal Survival Physiol Rev,2000;80:315.
[120] Kurapati.Increased hsp22 RNA Levels in Drosophila Lines Genetically Selected Increased Longevity. J Gerontol A Biol Sci Med Sci.2000, 55: 552-559
[121] Yanmei Zhao, Hui Sun, Jun LuXifespan extension and elevated hsp gene expression in Drosophila caused by histone deacetylase inhibitors Journal of Experimental Biology 2005,208, 697-705.
[122] Yanmei Zhao, Jun Lu, Hui Sun,et al. Histone acetylation regulates both transcription initiation and elongation of hsp22 gene in Drosophila Biochem Biophys Res Commun. 2005, 326:811-6
[123] Okazawa H.Polyglutamine diseases: a transcription disorder? Cell Mol Life Sci. 2003 Jul; 60(7): 1427-39.
[124] [Joonil Jung and Nancy Bonini CREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease.Science, 2007; 315: 1857 -1859
[125] Yoshitaka Nagai, Nobuhiro Fujikake, Katsuhito Ohno Prevention of polyglutam-ine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum. Mol. Genet., Jun 2003; 12: 1253-1259.
[1] http://flybase.org.
[2] http://nobelprize.org/nobel_prizes/medicine/
[3] St Johnston D. The art and design of genetic screens: Drosophila melanogaster. Nat Rev Genet, 2002, 3(3): 176-188.
[4] Brumby A M, Richardson H E. Using Drosophila melanogaster to map human cancer pathways. Nat Rev Cancer, 2005, 5(8): 626-639
[5] Letsou A, Bohmann D. Small flies—big discoveries: nearly a century of Dro sophia genetics and development. Dev Dyn, 2005, 232(3): 526-528.
[6] Rubin G M, Lewis E B. A brief history of Drosophila's contributions to genome research. Science, 2000, 287(5461): 2216-2218.
[7] Rubin G M, Yandell M D, Wortman J R, et al. Comparative genomics of the eukaryotes. Science, 2000, 287(5461): 2204-2215.
[8] 温艾，刘力 以果蝇模型研究人类神经退行性疾病 生物化学与生物物理进展 2003，30：357-361
[9] 万永奇，谢维 生命科学与人类疾病研究的重要模型——果蝇 生命科学2006，18(5)425-428。
[10] Manev H, Dimitrijevic N Dzitoyeva S. Techniques: fruit flies as models for neuropharmacological research. Trends Pharmacol Sci, 2003, 24(1): 41-43
[11] Bernards A, Hariharan I K. Of flies and men-studying human disease in Drosophila. Curr Opin Genet Dev, 2001, 11(3): 274-278
[12] Marsh, J.L. and Thompson, L.M. Can flies help humans treat neurodegen erative diseases? Bioessays 2004, 26, 485-496.
[13] Bonini, N.M. Drosophila as a genetic approach to human neurodeg- enerative disease. Parkinsonism Relat. Disord. 2001, 7, 171-175.
[14] Kazemi-Esfarjani, P. and Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 2000, 287, 1837-1840.
[15] Castle, W.E.Inbreeding, cross-breeding and sterility in Drosophila. Science 1906, 23: 153.
[16] Morgan, T.H. Sex limited inheritance in Drosophila. Science 1910, 32: 120--122.
[17] Morgan, T.H., Bridges, C.B. Sex-linked inheritance in Drosophila. Pubis Camegie Instn 1916, 237: 1--88.
[18] Bridges, C.B. Nondisjunction as. Proof of the chromosome theory of heredity. Genetics, 1916,1: 1-52,107-163.
[19] Sturtevant, Alfred H. The linear arrangement of six sex-linked factors in Drosophila, as shown by their mode of association. Journal of Experimental Biology, 1913,14:43-59.
[20] Bridges, C. B.. Direct proof through non. disjunction that the sex. linked genes of Drosophila are borne on the X-chromosome. Science, 1914,40: 107-109. 3.
[21] Bridges, C. B. Nondisjunction as a proof of the chromosome theory of heredity. Geneticsl916 1: 1-52,107-163.
[22] Muller HJ. Genetic variability, twin hybrids and constant hybrids in a case of balanced lethal factors. Genetics. 1918; 3:422-499.
[23] Muller H J.Artificial transmutation of the gene.Science, 1927, 66:84-87.
[24] Boris Ephrussi , G W Beadle Development of Eye Colors in Drosophila: Transplantation Experiments on the Interaction of Vermilion with Other Eye Colors. Genetics. 1937 ,22 (1):65-75 17246830
[25] Heitz E: Heterochromatin, chromocentren, chromomeren. Ber Deutsch Bot Ges 1929,47:274-284.
[26] Bauer, H.,Polytene Chromosome Structure in Relation to the "Folded Fibre" Concept. Naturwiss. 1938,26, 77.
[27] Painter, T. S., A new method for the study of chromosome aberrations and the plotting of chromosome maps in Drosophila melanogaster. Genetics, 1934, 19: 175-188.
[28] Bridges, C. B Salivary chromosome maps with a key to the banding of the chromosomes, of Drosophila melanogaster. J. Hered. 193526, 60-64.
[29] Bridges, C. B. 1938. 1938 A revised map of the salivary gland X-chromosome of Drosophila melanogaster. J. Hered. 29:. 11-13.
[30] Lewis, E.B. (1978). A gene complex controlling segmentation in Drosophila. Nature 276: 565-570.
[31] Nusslein-Volhard C, Wieschaus E. Mutation affecting segment number and polarity in Drosophila. Nature 1980; 287:795-80
[32] C.J. O'Kane & W.J. Gehring () Detection in situ of genomic regulatory elements in Drosophila. PNAS,1987, 84: 9123-9127.
[33] B G Hall.Selection-induced mutations occur in yeast. Proc Natl Acad Sci U S A. 1992 May 15; 89(10): 4300-4303.
[34] Brand A H, PERRIMON N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes[J]. Development, 1993,118:401-415
[35] Rubin G M, Spradling A C. Genetic transormation of Drosophilia with transposable element vectors. Science,1982,218:348-353
[36] Xu, T., Rubin, G.M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development, 1993,117(4): 1223-1237
[37] Hogness DS.Characterization of six cloned DNAs from Drosophila melanogaster, including one that contains the genes for rRNA. Cell 1975, 5(2): 149-157.W
[38] Lindsley DL Sandier L Segmental aneuploidy and the genetic gross structure of the Drosophila genome. Genetics 1972 71 157 184
[39] Wensink PC, Finnegan DJ, Donelson JE, Hogness DS. A system for mapping DNA sequences in the chromosomes of Drosophila melanogaster. Cell. 1974 Dec; 3(4):315-325.
[40] Misquitta, L., and Paterson, B.M. Targeted disruption of gene function in Dro -sophila by RNAinterference (RNAi): a role for nautilus in embryonic somatic muscle formation. Proc. Natl.Acad. Sci, 1999,96:1451-1456.
[41] Rong Y S,Golic K G.Gene targeting by homologous recombination in Drosophi la.Science,2000,288(5473):2013-2018
[42] Adams MD et al., The genome sequence of Drosophila melanogaster Science. 2000 Mar 24;287(5461):2185-95
[43] Lawrence T. Reiter, Lorraine Potocki, Sam Chien .Dissecting human disease in he postgenomic era. Science 2001; 291:1224-9.
[44] Winkelmann BR, Hager J A Systematic Analysis of Human Disease-Associated Gene Sequences In Drosophila melanogasterGenome Res. 2001 June; 11(6): 1114-1125.
[45] O'Kane CJ.Modelling human diseases in Drosophila and Caenorhabditis Semin Cell Dev Biol. 2003 Feb;14(1):3-10
[46] Lars Bertram, Rudolph E.The genetic epidemiology of neurodegenerative disease TanziJ Clin Invest, 2005,115(6): 1449-57
[47] Mayeux R.Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003;26: 81-104. Epub 2003 Jan 24.
[48] Mark P. Mattson. Pathways towards and away from Alzheimer's disease Nature.2004,430(5): 631-9
[49] Edward H Koo, Raphael Kopan. Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration Nat Med. 2004, July: S26-S33
[50] T. Tsuji, A. Shiozaki, etc Proteomic Profiling and Neurodegeneration in Alzheim er's disease Neurochem Res, 2002, 27(10): 1245-53
[51] Michael Paul Murphy etc. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production. Nat Med, 2005, 11(5): 545-50
[52] Miquel Vila, Serge Przedborski. Genetic clues to the pathogenesis of Parkinson's disease Nat Med, 2004, July: S58-S62
[53] Ted M. Dawson, Valina L. Dawsonl. Molecular Pathways of Neurodegeneration in Parkinson' s disease Science. 2003, 302: 917-22
[54] Yuzuru Imai, Ryosuke Takahashi. How do Parkin mutations result in neurodegeneration Curr Opin Neurobiol, 2004, 14: 384-389?
[55] Zhizhong Dong, Boris Ferger. Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1
[56] Manev H, Dimitrijevic N. Fruit flies for anti-pain drug discovery. Life Sci, 2005, 76(21): 2403-2407
[57] Manev H, Dimitrijevic N Dzitoyeva S. Techniques: fruit flies as models for neuropharmacological research. Trends Pharmacol Sci, 2003, 24(1): 41-43
[58] Bernards A, Hariharan I K. Of flies and men-studying human disease in Drosophila. Curr Opin Genet Dev, 2001, 11(3): 274-278
[59] Brumby A M, Richardson H E. Using Drosophila melanogaster to map human cancer pathways. Nat Rev Cancer, 2005, 5(8): 626-639
[60] Jackson, G.R., Salecker, I., Dong, X., Yao, X., Arnheim, N., Faber, P.W., MacDonald, M.E. and Zipursky, S.L. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron, 1998, 21, 633-642
[61] Ferber, D. Neurodegenerative disease. Using the fruit fly to model tau malfunction. Science, 2001, 292, 1983-1984
[62] Morwena Latouche, Christelle Lasbleiz, Elodie Martin, A Conditional Pan- Neu ronal Drosophila Model of Spinocerebellar Ataxia 7 with a Reversible Adult Phenotype Suitable for Identifying Modifier Genes J. Neurosci., Mar 2007, 27: 2483-2492.
[63] Warrick JM, Paulson HL, Gray-Board GL Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila Cell. 1998 Jun 12; 93(6):939-49.
[64] Takeyama, K, Ito, S, Yamamoto, A, Tanimoto, H, Furutani, T, Kanuka, H, Miura, M., Tabata, T. and Kato, S. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron, 2002, 35, 855-864.
[65] Pendleton, R.G., Parvez, F., Sayed, M. and Hillman, R. Effects of pharmacolog -ical agents upon a transgenic model of Parkinson's disease in Drosophila melanogaster. J. Pharmacol. Exp. Ther., 2002,300,91-96.
[66] Fernandez-Funez P, Nino-Rosales M L, de Gouyon B, et al. identifycation of genes that modify ataxin-1-induced neurodegenera tion. Nature, 2000, 408: 101-106
[67] Feany, M.B. and Bender, W.W. A Drosophila model of Parkinson's disease. Nature 2000, 404,394-398.
[6S] Bilen J, Bonini N M. Drosophila as a model for human neurodegenerative disease. Annu Rev Genet, 2005,39: 153-171
[69] Sang T K, Jackson G R. Drosophila models of neurodegenerative disease. NeuroRx, 2005,2(3): 438-446
[70] Fortini, M.E., Skupski, M.P., Boguski, M.S., and Hariharan, I.K. 2000. A survey of human disease gene counterparts in the Drosophila genome. J. Cell. Biol. 150: F23-30
[71] Salzberg, A. and Bellen, H.J. 1996. Invertebrate versus vertebrate neurogenesis: Variations on the same theme? Dev. Genet. 18: 1-10
[72] Chan, H.Y., Warrick, J.M., Gray-Board, et al.Mechanisms of chaperone suppression of polyglutamine disease: Selectivity, synergy and modulation of protein solubility in Drosophila. Hum. Mol. Genet. 2000 9,2811-2820.
[73] Bonini, N.M. Chaperoning brain degeneration. Proc. Natl. Acad. Sci. U.S.A. 2002 99 Suppl 4,16407-16411.
[74] Wolfgang, W.J, Miller, T, Webster, J.M, et al. A. Suppression of Huntington's disease pathology in Drosophila by human single-chain Fv antibodies. Proc. Natl. Acad. Sci. U.S.A. 2005, 102,11563-11568.
[75] Agrawal, N, Pallos, J, Slepko, N, et al. Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila. Proc. Natl.Acad. Sci.U.S.A.2005,102, 3777-3781
[76] Warrick, J.M, Chan, H.Y, Gray-Board, G.L, et al. Suppression of polyglutam -ine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet. 1999 , 23,425-428.
[77] Satterfield, T.F., Jackson, S.M., and Pallanck, L.J. A Drosophila homolog of the polyglutamine disease gene SCA2 is a dosage-sensitive regulator of actin filament formation. Genetics 2002, 162,1687-1702.
[78] Lee WC, Yoshihara M, Littleton JT. Cytoplasmic aggregates trap polyglutam-ne-containing proteins and block axonal transport in a Drosophila model of Huntington's disease. Proc Natl Acad Sci U S A, 2004,101(9): 3224-3229.
[79] Steffan, J.S., Bodai, L., Pallos, J. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001, 413, 739-743.
[80] Janny L ,Filip C.Forward genetics and map-based cloning approaches.Trends in Plant Science,2003,8:484-491.
[81] Adams M D, Sekelsky J J. From sequence to phenotype: reverse genetics in Drosophila melanogaster. Nat Rev Genet, 2002,3: 189-198.
[82] Orr HT, Chung MY, Banfi S, et al. Expansion of an unstable trinucleotide CAGrepeats in spinocerebellar ataxia type 1. Nat Genet, 1993,4(3):221-226.
[83] Pulst SM, Nechiporuk A, Nechiporuk T, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type2 .Nat Genet 1996,14(3): 269-276.
[84] Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet, 1994, 8(3): 221-228.
[85] Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet, 1997,15(1): 62-69.
[86] Lindblad K, Savontaus ML, Stevanin G, et al. An expanded CAG repeat sequence in spinocerebellar ataxia type 7. Genome Res, 1996,6(10): 965-971.
[87] Nakamura K, Jeong SY, Uchihara T, et al. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet, 2001,10(14): 1441-1448.
[88] Jana NR, Nukina N. Recent advances in understanding the pathogenesis of poly glutamine diseases: involvement of molecular chaperones and ubiquitin- proteasome pathway. J Chem Neuroanat, 2003,26(2):95-101.
[89] Amato.A, Prior.T, W.Barohn, Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology, 1993, 43: 791-794,
[90] Andrew S. E, Goldberg Y. P The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nature Genet, 1993, 4: 398 -403,
[91] Koide R, Ikeuchi T, Onodera O. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet, 1994, 6:9-13,
[92] Robert J. Ferrante, James K. Kubilus.Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's disease Mice. J Neurosci, 2003,23:9418-9427.
[93] Ghazaleh, Sadri-Vakili, Jang-Ho J. Cha .Mechanisms of Disease: histone modific -ations in Huntington's disease. Nature Clinical Practice Neurology 2006,2, 330-338.
[94] Jozsef P. Nemes, Kellie A. Benzow a, Michael D. Koob .The SCA8 transcriptis an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1) Human Molecular Genetics, 2000,9,1543-1551.
[95] Hong Jiang, Ami Mankodi, Maurice S. et al. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons Human Molecular Genetics 2004 13(24):3079-3088
[96] Jonathan M. Houseley , Zongsheng Wang, Graham J. R. Brock Myotonic dystrophy associated expanded CUG repeat muscleblind positive ribonuclear foci are not toxic to Drosophila Human Molecular Genetics 2005 14(6):873-883
[97] McBride S M, Choi C H, Wang Y, et al. Pharmacological rescue of s ynapticplasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron, 2005,45(5): 753-764.
[98] Jin P, Zarnescu D C, Zhang F P, et al. RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila Mechanisms of Disease.Neuron, 2003, 39(5): 739-747.
[99] Mark P. Mattson. Pathways towards and away from Alzheimer's disease Nature.2004,430(5): 631-9
[100] Yoo-Hun Suh and Frederic Checler Amyloid Precursor Protein, Presenilins, and a-Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's disease Pharmacol. Rev., Sep 2002; 54: 469.
[101] Dennis J. Selkoe Alzheimer's Disease: Genes, Proteins, and Therapy Physiol Rev, Apr 2001; 81: 741.
[102] Michael Paul Murphy, et al.Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production Nat Med, 2005, 11(5): 545-50
[103] Igor Klyubin, Dominic M Walsh etc. Amyloid Pprotein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo. Nat Med, 2005, 11(5): 556-613
[104] Peter J Nestor, Philip Scheltens etc. Advances in the early detection of Alzheimer's disease. Nat Neurosci, 2004, July: S34-S41
[105] James P Cleary, Dominic M Walsh etc. Natural oligomers of the amyloid-βprotein specifically disrupt cognitive function Nat Med 2005, 8(1): 79-84
[106] Craig A. Micchelli, William P. Esler, W. et al.g-Secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila FASEB J, Nov 2002; 10.1096.
[107] LQ Luo, LE Martin-Morris, and K White. Identification, secretion, and neural expression of APPL, a Drosophila protein similar to human amyloid protein precursorJ. Neurosci. Dec 1990; 10: 3849.
[108] Koichi Iijima, Hsin-Ping Liu, Ann-Shyn Chiang, et al. Hearn Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila: A potential model for Alzheimer's disease PNAS, 2004; 101: 6623 - 6628.
[109] Greeve, I., Kretzschmar, D., Tschape, et al.Age-dependent neurodegen- eration and Alzheimer-amyloid plaque formation in transgenic Drosophila. J. Neurosci. 2004, 24,3899-3906.
[110] De Jonghe, M Cruts, EA Rogaeva, Aberrant splicing in the presenilin-1 intron 4 mutations causes presenile Alzheimer's disease by increased Abeta42 secretion Hum. Mol. Genet, Aug 1999; 8: 1529 -1540.
[111] Anke Fossgreen, Bodo Bruckner, Christian Czech,Transgenic Drosophila exp -ressing human amyloid precursor protein show γ-secretase activity and a blistered-wing phenotype. PNAS,Nov 1998; 95: 13703.
[112] Miquel Vila, Serge Przedborski. Genetic clues to the pathogenesis of Park inson's disease Nat Med, 2004, July: S58-S62
[113] Bonifati V, Oostra BA, Heutink P. Linking DJ-1 to neurodegeneration offers novel insights for understanding the pathogenesis of Parkinson's disease.J Mol Med, 2004, 82:163-174
[114] Abbas N, Lucking CB, Ricard S,et al.A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. Hum Mol Genet, 1999, 8(4):567-574
[115] Hedrich K, Marder K, Harris J,et al.Evaluation of 50 probands with early -onset Parkinson's disease for Parkin mutations. Neurology, 2002, 58(8): 1239-1246
[116] West A, Periquet M, Lincoln S, et al.Complex relationship between Parkin mutations and Parkinson disease. Am J Med Genet, 2002,114(5):584-591
[117] Hedrich K, Djarmati A, Schafer N, et al.DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease. Neurology, 2004,62(3):389-394.
[118] Bonifati V, Rizzu P, van Baren MJ,et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science, 2003, 299(5604):256- 259.
[119] Hatano Y, Li Y, Sato K, Asakawa S,et al. Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol, 2004, 56:424-427.
[120] J essica C. Greene, Alexander J, Whitworth. Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis Hum. Mol. Genet.2005; 14: 799 -811.
[121] Chen, L. and Feany, M.B. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat. Neurosci 2005, 8, 657-663.
[122] Kitada T,Asakawa S,Hattori N,et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature,1998,392: 605-608
[123] Valente EM, Abou-Sleiman PM.Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1. Science, 2004,304: 1158-1160.
[124] Auluck, P.K., Meulener, M.C., and Bonini, N.M. Mechanisms of suppression of {alpha}-synuclein neurotoxicity by geldanamycin in Drosophila. J. Biol. Chem 2005,280,2873-2878.
[125] Auluck, P.K., Chan, H.Y., Trojanowski, et al. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 2002, 295,865-868.
[126] Klucken.J, Shin. Y, Masliah, et al. Hsp70 Reduces alpha-Synuclein Aggregation and Toxicity. J. Biol. Chem. 2004 , 279, 25497-25502.
[127] Yakov Pesah, Tuan Pham, Heather Burgess, et al.Drosophila parkin mutants have decreased mass and cell size and increased sensitive -ity to oxygen radical stress Development, 2004, 131:2183-2194.
[128] Sang TK, Chang HY, Lawless GM .Drosophila model of mutant human parkin -induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine. J Neurosci, 2007 27:981-92.
[129] Ira E. Clark, Mark W. Dodson, Changan Jiang et al.Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin . Nature,2006 ,441:1162-1166
[130] Yufeng Yang, Stephan Gehrke, Yuzuru Imai et al.Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pinkl is rescued by Parkin .PNAS, Jul 2006; 103: 10793 10798.
[131] Fiona M. Menzies Sarat C. Yenisetti and Kyung-Tai Min et al. Roles of b Drosophila DJ-1 in Survival of Dopaminergic Neurons and Oxidative Stress.Current biology 2005, 6:1578-1582.
[132] Marc C. Meulener, Kexiang Xu, Leonor .Thomson et al. Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. PNAS, 2006,103:12517-12522.
[133] Melissa Lee Phillips.Parkinson Disease: PD Gene and Oxidative StressEnviron Health Perspect. 2006,114: A96.
[2] Serge Przedborski, Miquel Vila etc. Neurodegeneration: What is it and where are we J Clin Invest. 2003,111(1): 3-10
[3] Lars Bertram, Rudolph E.The genetic epidemiology of neurodegenerative disease TanziJ Clin Invest, 2005,115(6): 1449-57
[4] Mayeux R.Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003 ;26: 81-104. Epub 2003 Jan 24.
[5] Mark P. Mattson. Pathways towards and away from Alzheimer's disease Nature.2004,430(5): 631-9
[6] Edward H Koo, Raphael Kopan. Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration Nat Med.2004, July: S26-S33
[7] T. Tsuji, A. Shiozaki, etc Proteomic Profiling and Neurodegeneration in Alzheimer's disease Neurochem Res, 2002,27(10): 1245-53
[8] Michael Paul Murphy etc.Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production Nat Med, 2005, 11(5): 545-50
[9] Miquel Vila, Serge Przedborski. Genetic clues to the pathogenesis of Parkinson's disease Nat Med, 2004, July: S58-S62
[10] Ted M. Dawson, Valina L. Dawsonl. Molecular Pathways of Neurodegeneration in Parkinson's disease Science.2003,302: 917-22
[11] Yuzuru Imai, Ryosuke Takahashi.How do Parkin mutations result in neurodegeneration Curr Opin Neurobiol, 2004,14:384-389?
[12] Zhizhong Dong, Boris Ferger. Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-l.PNAS, 2003, 100(21):12438-12443.
[13] Seppi K, Yekhlef F, Diem A, et al. Progression of parkinsonism in multiple s ystem atrophy. J Neurol 2005; 252:91-6.
[14] Vanacore N, Bonifati V, Fabbrini G, et al. Case-control study of multiple system atrophy. Mov Disord 2005; 20:158-63.
[15] Watanabe H, Saito Y, Terao S, et al. Progression and prognosis in multiple system atrophy: An analysis of 230 Japanese patients. Brain 2002,125:1070-1083.
[16] Shaw PJ. Molecular and cellular pathways of neurodegeneration in motor neurone disease. J Neurol Neurosurg Psychiatry. 2005 Aug;76(8): 1046-57.
[17] The molecular genetics of non-ALS motor neuron diseases. Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):986-1000.
[18] S. Maekawa, S. Al-Sarraj, M. Kibble. Cortical selective vulnerability in motor neuron disease: a morphometric study Brain, Jun 2004; 127: 1237 -1251.
[19] Orr HT, Chung MY, Banfi S, et al. Expansion of an unstable trinucleotide CAGrepeats in spinocerebellar ataxia type 1. Nat Genet, 1993,4(3):221-226.
[20] Pulst SM, Nechiporuk A, Nechiporuk T, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type2 .Nat Genet 1996,14(3): 269-276.
[21] [21] Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet, 1994, 8(3): 221-228.
[22] Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet, 1997,15(1): 62-69.
[23] Lindblad K, Savontaus ML, Stevanin G, et al. An expanded CAG repeat sequence in spinocerebellar ataxia type 7. Genome Res, 1996,6(10): 965-971.
[24] Nakamura K, Jeong SY, Uchihara T, et al. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet, 2001,10(14): 1441-1448.
[25] Jana NR, Nukina N. Recent advances in understanding the pathogenesis of poly glutamine diseases: involvement of molecular chaperones and ubiquitin-proteasome pathway. J Chem Neuroanat, 2003,26(2):95-101.
[26] Amato.A,Prior.T,W.Barohn, Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology, 1993,43: 791-794,
[27] Andrew S. E, Goldberg Y. PThe relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nature Genet, 1993, 4: 398 -403.
[28] Koide R, Ikeuchi T, Onodera O. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet, 1994, 6:9-13,
[29] Andrew S. E, Goldberg Y. P The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nature Genet, 1993, 4: 398 -403,
[30] Kazemi-Esfarjani, P. and Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science, 2000,287,1837-1840.
[31] Jill Heemskerk, Allan J. etc From chemical to drug: neurodegeneration drug screening and the ethics clinical trials Jill Heemskerk, Allan J. etc.Nat neurosci suppl, 2002, 5: 1027-9.
[32] Haibin Xia, Qinwen Mao etc RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia.Nat Med. 2004, 10(8): 816-20.
[33] Olle Lindvall, Zaal Kokaia etc. Stem cell therapy for human neurodegenerative disorders-how to make it work Nat Med.2004, July: S42-S50.
[34] Matthias Rothermundt, Marion Peters etc S100B in Brain Damage and Neurodegeneration Microsc Res Tech. 2003, 60:614-32 .
[35] Leo H.Wang, Cagri G. MIXED-LINEAGE KINASES: A Target for the Prevention of Neurodegeneration Annu Rev Pharmacol Toxicol., 2004, 44: 451-74.
[36] Amato.A, Prior.T, W.Barohn, Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology, 1993, 43: 791-794,
[37] Michalik A, Van Broeckhoven C. Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet, 2003, 12,Spec No 2:R173-186.
[38] Bates G. Huntingtin aggregation and toxicity in Huntington's disease. Lancet, 2003,361(9369): 1642-1644.
[39] Arrasate M, Mitra S, Schweitzer ES, et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature, 2004, 431(7010): 805-810.
[40] Cowan KJ, Diamond MI, Welch WJ. Polyglutamine protein aggregation and toxicity are linked to the cellular stress response. Hum Mol Genet, 2003, 12(12): 1377-1391.
[41] Lee WC, Yoshihara M, Littleton JT. Cytoplasmic aggregates trap polyglu-tamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease. Proc Natl Acad Sci U S A, 2004,101(9): 3224-3229.
[42] Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease Nat Med, 2004,10 Suppl: S10-7.
[43] Jiang H, Tang BS, Xu B, Zhao GH, Shen L, Tang JG, Li QH, Xia K.Frequency analysis of autosomal dominant spinocerebellar ataxias in mainland Chinese patients and clinical and molecular characterization of spinocerebellar ataxia type 6.Chin Med J (Engl). 2005 May 20; 118(10):837-43.
[44] Jiang M, Jin CL, Lin CK, Qiu GR, Liu ZL, Wang CX, Sun KL.Analysis and application of SCA1 and SCA3/MJD gene CAG repeats in Han population in Northeastern China Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2004 Feb; 21(1):83-5.
[45] Matsumura R, Futamura N, Ando N, Ueno S.Frequency of spinocerebellar ataxia mutations in the Kinki district of Japan. Acta Neurol Scand. 2003 Jan; 107(l):38-41.
[46] Basu P, Chattopadhyay B, Gangopadhaya PK, Mukherjee SC, Sinha KK, Das SK, Roychoudhury S, Majumder PP, Bhattacharyya NP.Analysis of CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci in spinocerebellar ataxia patients and distribution of CAG repeats at the SCA1, SCA2 and SCA6 loci in nine ethnic populations of eastern India.Hum Genet. 2000 Jun;106(6):597-604.
[47] Tang BS, Liu C, Shen L, et al. Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. Arch Neurol 2000; 57:540-544.
[48] Shimizu Y, Yoshida K, Okano T, Ohara S, Hashimoto T, Fukushima Y, Ikeda S.Regional features of autosomal-dominant cerebellar ataxia in Nagano: clinical and molecular genetic analysis of 86 families. J Hum Genet. 2004;49(11):610-6. Epub 2004 Oct 8.
[49] Kubis N, Durr A, Gugenheim M, Chneiweiss H, Mazzetti P, Briee A, Bouche P.Polyneuropathy in autosomal dominant cerebellar ataxias: phenotype- genotype correlation.Muscle Nerve. 1999 Jun;22(6):712
[50] Chowdary TK, Raman B, Ramakrishna T, et al.Mammalian Hsp22 is a heat -inducible small heat-shock protein with chaperone-like activity. Biochem J, 2004, 381 (Pt 2): 379-387
[51] Gober MD, Depre C, Aurelian L. Correspondence regarding M. V. Kim et al. "Some properties of human small heat shock protein Hsp22 (H11 or HspB8)". Biochem Biophys Res Commun, 2004, 321(2): 267-268.
[52] Tao D, Lu J, Sun H, et al. Trichostatin A extends the lifespan of Drosophila melanogaster by elevating Hsp22 expression Acta Biochimica et Biophysia Sinica, 2004, 36: 618-622.
[53] Sun X, Fontaine JM, Rest JS, et al. Interaction of human HSP22 (HSPB8) with other small heat shock proteins. J Biol Chem. 2004,279(4): 2394-2402.
[54] Kurapati Passananti H B, Rose M R, et al. Increased Hsp22 RNA levels in Drosophila lines genetically selected for increased longevity Gerontol. A Biol.Sci. Med. Sci., 2000, 55: 552-559.
[55] Morrow G, Samson M, Michaud S, et al. Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress.The FASEB J, 2004,18:598-599.
[56] King V, Tower J. Aging-specific expression of Drosophila Hsp22. Devel Biol. 1999,207: 107-118.
[57] Rubin G M, Lewis E B. A brief history of Drosophila's contributions to genome research. Science, 2000,287(5461):2216-2218
[58] St Johnston D. The art and design of genetic screens: Drosophila melanogaster. Nat Rev Genet, 2002, 3(3): 176-188
[59] Winkelmann BR, Hager J A Systematic Analysis of Human Disease-Associated Gene Sequences In Drosophila melanogasterGenome Res. 2001 June; 11(6): 1114-1125.
[60] O'Kane CJ.Modelling human diseases in Drosophila and Caenorhabditis Semin Cell Dev Biol. 2003 Feb;14(1):3-10
[61] Lengyel J A, Iwaki D D. It takes guts: the Drosophila hind-gut as a model system for organogenesis. Dev Biol, 2002,243(1): 1-19
[62] Buchanan, R.L. and Benzer, S. Defective glia in the Drosophila brain degeneration mutant drop-dead. Neuron, 1993, 10, 839-850 .
[63] Kretzschmar, D., Hasan, G., Sharma, S., Heisenberg, M., and Benzer, S. The swiss cheese mutant causes glial hyperwrapping and brain degeneration in Drosophila. J. Neurosci. 1997,17,7425-7432
[64] Palladino, M.J., Bower, J.E., Kreber, R., and Ganetzky, B. Neural dysfunction and neurodegeneration in Drosophila Na+/K+ ATPase alpha subunit mutants. J. Neurosci. 2003,23,1276-1286
[65] Trotta, N., Orso, G., Rossetto, M.G., Daga, A., and Broadie, K. The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function. Curr. Biol. 2004, 14,1135-1147.
[66] Jackson, G.R., Salecker, I., Dong, X., Yao, X., Arnheim, N., Faber, P.W., MacDonald, M.E. and Zipursky, S.L. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron, 1998,21, 633-642
[67] Terrence F. Satterfield, Stephen A .Drosophila Homolog of the Polyglutamine Disease Gene SCA2 Is a Dosage-Sensitive Regulator of Actin Filament Formation Genetics, Vol. 162,1687-1702, December 2002, Copyright (?) 2002
[68] Morwena Latouche, Christelle Lasbleiz, Elodie Martin,A Conditional Pan-Neu ronal Drosophila Model of Spinocerebellar Ataxia 7 with a Reversible Adult Phenotype Suitable for Identifying Modifier Genes J. Neurosci., Mar 2007,27: 2483 - 2492.
[69] Warrick JM, Paulson HL, Gray-Board GL Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila Cell. 1998 Jun 12; 93(6):939-49.
[70] Brand, A.H., Perrimon, N., 1993. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development, 118(2):401-415.
[71] Serggio Lanata. Head Involution Defective (hid) Iap Antagonist - A Possible Transcriptional Gene Target for Tumor Suppressor Gene p53 Journal of Undergraduate Research, 2003,435: 156-178.
[72] Fernandez-Funez P, Nino-Rosales M L, de Gouyon B, et al. identifycation of genes that modify ataxin-1 -induced neurodegenera tion. Nature, 2000, 408: 101-106.
[73] Feany, M.B. and Bender, W.W. A Drosophila model of Parkinson's disease. Nature 2000, 404,394-398.
[74] Takeyama, K, Ito, S, Yamamoto, A, Tanimoto, H, Furutani, T, Kanuka, H, Miura, M., Tabata, T. and Kato, S. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron, 2002,35, 855-864.
[75] Phelps CB, Brand AH. Ectopic gene expression in Drosophila using GAL4system. Methods, 1998, 14(4): 367-379
[76] Wilder E. Ectopic expression in Drosophila. Methods Mol Biol., 2000, 137: 9-14.
[77] Lin, D.M. and Goodman, C.S., 1994. Ectopic and increased expression of Fasciclin Ⅱ alters motoneuron growth cone guidance. Neuron 13, pp. 507-523.
[78] Fortini M E, Bonini N M. Modeling human neurodegenenrative diseases in Drosophila. Trends in Genetics, 2000, 16 (4): 161-167.
[79] Paul Mark B. Medina, Lance L. SwickA Novel Forward Genetic Screen for Identifying Mutations Affecting Larval Neuronal Dendrite Development in Drosophila melanogaster Genetics. 2006 April; 172(4): 2325-2335
[80] Knud Nairz, Peder Zipperlen, Charles Dearolf. A reverse genetic screen in Drosophila using a deletion-inducing mutagen Genome Biol. 2004; 5(10): R83.
[81] Yong Q. Zhang David B. Friedman Zhe Wang Protein Expression Profiling of the Drosophila Fragile X Mutant Brain Reveals Up-regulation of Monoamine Synthesis Mol. Cell. Proteomics 4: 278-290, 2005.
[82] Muller H.j. Genetic variability, twin hybrids and constant hybrids, in. a case of balanced lethal factors. Genetics 1918; 3: 422-499
[83] Koshy, B.T. and Zoghbi, H.Y. The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis. Brain Pathol, 1997, 7: 927-942.
[84] Paulson, H.L. Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis) fold. Am. J. Hum. Genet. 1999, 64: 339-345.
[85] http://flybase.org.
[86] Durr A, Stevanin G, Cancel G. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular and neuropathologic features. Ann. Neurol., 1996, 39: 490-499.
[87] Joonil Jung and Nancy Bonini CREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease. Science, 2007, 315: 1857-1859.
[88] Bernd O. Evert, Julieta Araujo, Ana M. Ataxin-3 Represses Transcription via Chromatin Binding, Interaction with Histone Deacetylase 3, and Histone Deacetylation. J. Neurosci., 2006, 26: 11474 - 11486.
[89] Brigit E. Riley and Harry T Orr. Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle. Genes & Dev, 2006, 20: 2183-2192.
[90] Norma M. Wills and John F. Atkins The potential role of ribosomal frameshifting in generating aberrant proteins implicated in neurodegenerative diseases.RNA, 2006,12: 1149 -1153.
[91] Gretta Abou-Sleymane, Frederic Chalmel, Dominique Helmlinger et al. Polyglutamine expansion causes neurodegeneration by altering the neuronal differentiation program.Hum. Mol. Genet, Mar 2006,15: 691 - 703.
[92] Annette Haacke, Sarah A. Broadley, Raina Boteva, et al.Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3.Hum. Mol. Genet, 2006,15: 555 - 568.
[93] S Tabrizi. Neurodegenerative diseases neurobiology pathogenesis and therapeutics. J. Neurol. Neurosurg. Psychiatry, 2006,77: 284.
[94] Kezhong Zhang and Randal J. Kaufman .The unfolded protein response: A stress signaling pathway critical for health and disease. Neurology, Jan 2006; 66:S102-S109
[95] Stephen C . Meredith .Protein Denaturation and Aggregation: Cellular Responses to Denatured and Aggregated Proteins. Ann. N.Y. Acad. Sci., 2005,1066:181-221.
[96] Aaron B. Bowman, Seung-Yun Yoo, Nico P. Dantuma, et al. Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation.Hum. Mol. Genet, 2005,14: 679 - 691.
[97] Daniel Goti, Scott M. Katzen, Jesse Mez, et al. A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical ConcentrationJ. Neurosci, 2004,24:10266-10279
[98] Yeon-jeong Kim .Role of Polyunsaturated Fatty Acids for Misfolding Protein Aggregations: Implication for Neurodegenerative Diseases.Ann. N.Y. Acad. Sci., 2006; 1086: 11-20
[99] Tapan K Chaudhuri and Subhankar. Paul.Protein-misfolding diseases and chaperone-based therapeutic approaches. FEBS J. 2006,273: 1331 - 1349
[100] Jasna Brujic, Rodolfo I. Z. Hermans, et al.Dwell-Time Distribution Analysis of Polyprotein Unfolding Using Force-Clamp Spectroscopy.Biophys. J. 2007, 92: 2896 - 2903.
[101] Michelle K. M. Chow, Andrew M. Ellisdon,et al.Polyglutamine Expansion in Ataxin-3 Does Not Affect Protein Stability: IMPLICATIONS FOR MISFOLDING AND DISEASE. J. Biol. Chem.2004,279: 47643 - 47651.
[102] Valerie Askanas and W. King Engel. Inclusion-body myositis: A myodegen erative conformational disorder associated with Aβ, protein misfolding, and proteasome inhibition. Neurology, 2006; 66: S39 - S48.
[103] Barnaby C.H. May, Cedric Govaerts, Fred E.Cohen Developing therapeutics for the diseases of protein misfolding. Neurology, 2006, 66: S118 - S122 Hum. Mol. Genet. 2003,12: 3195 - 3205.
[104] Arjan Quist, Ivo Doudevski, Hai Lin, Rushana Azimova,et al.Amyloid ion channels: A common structural link for protein-misfolding disease .PNAS, 2005,102: 10427-10432
[105] Hilal A. Lashuel.Membrane Permeabilization: A Common Mechanism in Protein-Misfolding Diseases. Sci, Aging, Knowl. Environ. 2005; 2005: pe28.
[106] Ian V. J. Murray, Liu Liu, Hiroaki Komatsu,et al. Membrane-mediated Amyloidogenesis and the Promotion of Oxidative Lipid Damage by Amyloid βProteins.J. Biol. Chem., Mar 2007; 282: 9335 - 9345.
[107] Stephanie L. H. Miller, Erica L. Scappini.Ubiquitin-interacting Motifs Inhibit Aggregation of PolyQ-expanded Huntingtin J. Biol. Chem. 2007,282: 10096 - 10103.
[108] Jana NR, Nukina N. Recent advances in understanding the pathogenesis of poly glutamine diseases: involvement of molecular chaperones and ubiquitin protea- some pathway. J Chem Neuroanat, 2003,26(2):95-101.
[109] Tapan K Chaudhuri and Subhankar Paul Protein-misfolding diseases and chaperone-based therapeutic approaches .FEBS J. 2006,273: 1331 -1349.
[110] Yaohui Chai, Stacia L. Koppenhafer, Nancy M. Bonini,et al. Analysis of the Role of Heat Shock Protein (Hsp) Molecular Chaperones in Polyglutamine Disease.J.Neurosci. 1999; 19: 10338.
[111] Hideki Sakahira, Peter Breuer, Manajit K. Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. PNAS, 2002,99: 16412.
[112] Konstanze F. Winklhofer, Iris H. Henn, Penelope C ,et al.Inactivation of Parkin by Oxidative Stress and C-terminal Truncations: A PROTECTIVE ROLE OF MOLECULAR CHAPERONES. J. Biol. Chem, 2003, 278: 47199 - 47208.
[113] H.Y. Edwin Chan, John M. Warrick, Gladys L,et al..Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila.Hum. Mol. Genet., 2000, 9: 2811 - 2820.
[114] Hiroaki Adachi, Masahisa Katsuno, Makoto Minamiyama,et al.Heat Shock Protein 70 Chaperone Overexpression Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model by Reducing Nuclear-Localized Mutant Androgen Receptor Protein.J. Neurosci. 2003; 23: 2203.
[115] Paul J. Muchowski, Gregor Schaffar, Annie Sittler,et al.Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils.PNAS, 2000; 97: 7841.
[116] David F. Smith, Luke Whitesell, and Emmanuel Katsanis Molecular Chaperones: Biology and Prospects for Pharmacological Intervention. Pharmacol. 1998; 50: 493
[117] Serena Carra, Mitchel Sivilotti, Aura T. Chavez Zobel .HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells.Hum. Mol. Genet,2005,14: 1659 - 1669
[118] Yu Sun, Thomas H. MacRae. The small heat shock proteins and their role in human disease.FEBS J. 2005,272: 2613 - 2627.
[119] David G. Nicholls and Samantha L. Budd Mitochondria and Neuronal Survival Physiol Rev,2000;80:315.
[120] Kurapati.Increased hsp22 RNA Levels in Drosophila Lines Genetically Selected Increased Longevity. J Gerontol A Biol Sci Med Sci.2000, 55: 552-559
[121] Yanmei Zhao, Hui Sun, Jun LuXifespan extension and elevated hsp gene expression in Drosophila caused by histone deacetylase inhibitors Journal of Experimental Biology 2005,208, 697-705.
[122] Yanmei Zhao, Jun Lu, Hui Sun,et al. Histone acetylation regulates both transcription initiation and elongation of hsp22 gene in Drosophila Biochem Biophys Res Commun. 2005, 326:811-6
[123] Okazawa H.Polyglutamine diseases: a transcription disorder? Cell Mol Life Sci. 2003 Jul; 60(7): 1427-39.
[124] [Joonil Jung and Nancy Bonini CREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease.Science, 2007; 315: 1857 -1859
[125] Yoshitaka Nagai, Nobuhiro Fujikake, Katsuhito Ohno Prevention of polyglutam-ine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum. Mol. Genet., Jun 2003; 12: 1253-1259.
[1] http://flybase.org.
[2] http://nobelprize.org/nobel_prizes/medicine/
[3] St Johnston D. The art and design of genetic screens: Drosophila melanogaster. Nat Rev Genet, 2002, 3(3): 176-188.
[4] Brumby A M, Richardson H E. Using Drosophila melanogaster to map human cancer pathways. Nat Rev Cancer, 2005, 5(8): 626-639
[5] Letsou A, Bohmann D. Small flies—big discoveries: nearly a century of Dro sophia genetics and development. Dev Dyn, 2005, 232(3): 526-528.
[6] Rubin G M, Lewis E B. A brief history of Drosophila's contributions to genome research. Science, 2000, 287(5461): 2216-2218.
[7] Rubin G M, Yandell M D, Wortman J R, et al. Comparative genomics of the eukaryotes. Science, 2000, 287(5461): 2204-2215.
[8] 温艾，刘力 以果蝇模型研究人类神经退行性疾病 生物化学与生物物理进展 2003，30：357-361
[9] 万永奇，谢维 生命科学与人类疾病研究的重要模型——果蝇 生命科学2006，18(5)425-428。
[10] Manev H, Dimitrijevic N Dzitoyeva S. Techniques: fruit flies as models for neuropharmacological research. Trends Pharmacol Sci, 2003, 24(1): 41-43
[11] Bernards A, Hariharan I K. Of flies and men-studying human disease in Drosophila. Curr Opin Genet Dev, 2001, 11(3): 274-278
[12] Marsh, J.L. and Thompson, L.M. Can flies help humans treat neurodegen erative diseases? Bioessays 2004, 26, 485-496.
[13] Bonini, N.M. Drosophila as a genetic approach to human neurodeg- enerative disease. Parkinsonism Relat. Disord. 2001, 7, 171-175.
[14] Kazemi-Esfarjani, P. and Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 2000, 287, 1837-1840.
[15] Castle, W.E.Inbreeding, cross-breeding and sterility in Drosophila. Science 1906, 23: 153.
[16] Morgan, T.H. Sex limited inheritance in Drosophila. Science 1910, 32: 120--122.
[17] Morgan, T.H., Bridges, C.B. Sex-linked inheritance in Drosophila. Pubis Camegie Instn 1916, 237: 1--88.
[18] Bridges, C.B. Nondisjunction as. Proof of the chromosome theory of heredity. Genetics, 1916,1: 1-52,107-163.
[19] Sturtevant, Alfred H. The linear arrangement of six sex-linked factors in Drosophila, as shown by their mode of association. Journal of Experimental Biology, 1913,14:43-59.
[20] Bridges, C. B.. Direct proof through non. disjunction that the sex. linked genes of Drosophila are borne on the X-chromosome. Science, 1914,40: 107-109. 3.
[21] Bridges, C. B. Nondisjunction as a proof of the chromosome theory of heredity. Geneticsl916 1: 1-52,107-163.
[22] Muller HJ. Genetic variability, twin hybrids and constant hybrids in a case of balanced lethal factors. Genetics. 1918; 3:422-499.
[23] Muller H J.Artificial transmutation of the gene.Science, 1927, 66:84-87.
[24] Boris Ephrussi , G W Beadle Development of Eye Colors in Drosophila: Transplantation Experiments on the Interaction of Vermilion with Other Eye Colors. Genetics. 1937 ,22 (1):65-75 17246830
[25] Heitz E: Heterochromatin, chromocentren, chromomeren. Ber Deutsch Bot Ges 1929,47:274-284.
[26] Bauer, H.,Polytene Chromosome Structure in Relation to the "Folded Fibre" Concept. Naturwiss. 1938,26, 77.
[27] Painter, T. S., A new method for the study of chromosome aberrations and the plotting of chromosome maps in Drosophila melanogaster. Genetics, 1934, 19: 175-188.
[28] Bridges, C. B Salivary chromosome maps with a key to the banding of the chromosomes, of Drosophila melanogaster. J. Hered. 193526, 60-64.
[29] Bridges, C. B. 1938. 1938 A revised map of the salivary gland X-chromosome of Drosophila melanogaster. J. Hered. 29:. 11-13.
[30] Lewis, E.B. (1978). A gene complex controlling segmentation in Drosophila. Nature 276: 565-570.
[31] Nusslein-Volhard C, Wieschaus E. Mutation affecting segment number and polarity in Drosophila. Nature 1980; 287:795-80
[32] C.J. O'Kane & W.J. Gehring () Detection in situ of genomic regulatory elements in Drosophila. PNAS,1987, 84: 9123-9127.
[33] B G Hall.Selection-induced mutations occur in yeast. Proc Natl Acad Sci U S A. 1992 May 15; 89(10): 4300-4303.
[34] Brand A H, PERRIMON N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes[J]. Development, 1993,118:401-415
[35] Rubin G M, Spradling A C. Genetic transormation of Drosophilia with transposable element vectors. Science,1982,218:348-353
[36] Xu, T., Rubin, G.M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development, 1993,117(4): 1223-1237
[37] Hogness DS.Characterization of six cloned DNAs from Drosophila melanogaster, including one that contains the genes for rRNA. Cell 1975, 5(2): 149-157.W
[38] Lindsley DL Sandier L Segmental aneuploidy and the genetic gross structure of the Drosophila genome. Genetics 1972 71 157 184
[39] Wensink PC, Finnegan DJ, Donelson JE, Hogness DS. A system for mapping DNA sequences in the chromosomes of Drosophila melanogaster. Cell. 1974 Dec; 3(4):315-325.
[40] Misquitta, L., and Paterson, B.M. Targeted disruption of gene function in Dro -sophila by RNAinterference (RNAi): a role for nautilus in embryonic somatic muscle formation. Proc. Natl.Acad. Sci, 1999,96:1451-1456.
[41] Rong Y S,Golic K G.Gene targeting by homologous recombination in Drosophi la.Science,2000,288(5473):2013-2018
[42] Adams MD et al., The genome sequence of Drosophila melanogaster Science. 2000 Mar 24;287(5461):2185-95
[43] Lawrence T. Reiter, Lorraine Potocki, Sam Chien .Dissecting human disease in he postgenomic era. Science 2001; 291:1224-9.
[44] Winkelmann BR, Hager J A Systematic Analysis of Human Disease-Associated Gene Sequences In Drosophila melanogasterGenome Res. 2001 June; 11(6): 1114-1125.
[45] O'Kane CJ.Modelling human diseases in Drosophila and Caenorhabditis Semin Cell Dev Biol. 2003 Feb;14(1):3-10
[46] Lars Bertram, Rudolph E.The genetic epidemiology of neurodegenerative disease TanziJ Clin Invest, 2005,115(6): 1449-57
[47] Mayeux R.Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003;26: 81-104. Epub 2003 Jan 24.
[48] Mark P. Mattson. Pathways towards and away from Alzheimer's disease Nature.2004,430(5): 631-9
[49] Edward H Koo, Raphael Kopan. Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration Nat Med. 2004, July: S26-S33
[50] T. Tsuji, A. Shiozaki, etc Proteomic Profiling and Neurodegeneration in Alzheim er's disease Neurochem Res, 2002, 27(10): 1245-53
[51] Michael Paul Murphy etc. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production. Nat Med, 2005, 11(5): 545-50
[52] Miquel Vila, Serge Przedborski. Genetic clues to the pathogenesis of Parkinson's disease Nat Med, 2004, July: S58-S62
[53] Ted M. Dawson, Valina L. Dawsonl. Molecular Pathways of Neurodegeneration in Parkinson' s disease Science. 2003, 302: 917-22
[54] Yuzuru Imai, Ryosuke Takahashi. How do Parkin mutations result in neurodegeneration Curr Opin Neurobiol, 2004, 14: 384-389?
[55] Zhizhong Dong, Boris Ferger. Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1
[56] Manev H, Dimitrijevic N. Fruit flies for anti-pain drug discovery. Life Sci, 2005, 76(21): 2403-2407
[57] Manev H, Dimitrijevic N Dzitoyeva S. Techniques: fruit flies as models for neuropharmacological research. Trends Pharmacol Sci, 2003, 24(1): 41-43
[58] Bernards A, Hariharan I K. Of flies and men-studying human disease in Drosophila. Curr Opin Genet Dev, 2001, 11(3): 274-278
[59] Brumby A M, Richardson H E. Using Drosophila melanogaster to map human cancer pathways. Nat Rev Cancer, 2005, 5(8): 626-639
[60] Jackson, G.R., Salecker, I., Dong, X., Yao, X., Arnheim, N., Faber, P.W., MacDonald, M.E. and Zipursky, S.L. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron, 1998, 21, 633-642
[61] Ferber, D. Neurodegenerative disease. Using the fruit fly to model tau malfunction. Science, 2001, 292, 1983-1984
[62] Morwena Latouche, Christelle Lasbleiz, Elodie Martin, A Conditional Pan- Neu ronal Drosophila Model of Spinocerebellar Ataxia 7 with a Reversible Adult Phenotype Suitable for Identifying Modifier Genes J. Neurosci., Mar 2007, 27: 2483-2492.
[63] Warrick JM, Paulson HL, Gray-Board GL Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila Cell. 1998 Jun 12; 93(6):939-49.
[64] Takeyama, K, Ito, S, Yamamoto, A, Tanimoto, H, Furutani, T, Kanuka, H, Miura, M., Tabata, T. and Kato, S. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron, 2002, 35, 855-864.
[65] Pendleton, R.G., Parvez, F., Sayed, M. and Hillman, R. Effects of pharmacolog -ical agents upon a transgenic model of Parkinson's disease in Drosophila melanogaster. J. Pharmacol. Exp. Ther., 2002,300,91-96.
[66] Fernandez-Funez P, Nino-Rosales M L, de Gouyon B, et al. identifycation of genes that modify ataxin-1-induced neurodegenera tion. Nature, 2000, 408: 101-106
[67] Feany, M.B. and Bender, W.W. A Drosophila model of Parkinson's disease. Nature 2000, 404,394-398.
[6S] Bilen J, Bonini N M. Drosophila as a model for human neurodegenerative disease. Annu Rev Genet, 2005,39: 153-171
[69] Sang T K, Jackson G R. Drosophila models of neurodegenerative disease. NeuroRx, 2005,2(3): 438-446
[70] Fortini, M.E., Skupski, M.P., Boguski, M.S., and Hariharan, I.K. 2000. A survey of human disease gene counterparts in the Drosophila genome. J. Cell. Biol. 150: F23-30
[71] Salzberg, A. and Bellen, H.J. 1996. Invertebrate versus vertebrate neurogenesis: Variations on the same theme? Dev. Genet. 18: 1-10
[72] Chan, H.Y., Warrick, J.M., Gray-Board, et al.Mechanisms of chaperone suppression of polyglutamine disease: Selectivity, synergy and modulation of protein solubility in Drosophila. Hum. Mol. Genet. 2000 9,2811-2820.
[73] Bonini, N.M. Chaperoning brain degeneration. Proc. Natl. Acad. Sci. U.S.A. 2002 99 Suppl 4,16407-16411.
[74] Wolfgang, W.J, Miller, T, Webster, J.M, et al. A. Suppression of Huntington's disease pathology in Drosophila by human single-chain Fv antibodies. Proc. Natl. Acad. Sci. U.S.A. 2005, 102,11563-11568.
[75] Agrawal, N, Pallos, J, Slepko, N, et al. Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila. Proc. Natl.Acad. Sci.U.S.A.2005,102, 3777-3781
[76] Warrick, J.M, Chan, H.Y, Gray-Board, G.L, et al. Suppression of polyglutam -ine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet. 1999 , 23,425-428.
[77] Satterfield, T.F., Jackson, S.M., and Pallanck, L.J. A Drosophila homolog of the polyglutamine disease gene SCA2 is a dosage-sensitive regulator of actin filament formation. Genetics 2002, 162,1687-1702.
[78] Lee WC, Yoshihara M, Littleton JT. Cytoplasmic aggregates trap polyglutam-ne-containing proteins and block axonal transport in a Drosophila model of Huntington's disease. Proc Natl Acad Sci U S A, 2004,101(9): 3224-3229.
[79] Steffan, J.S., Bodai, L., Pallos, J. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001, 413, 739-743.
[80] Janny L ,Filip C.Forward genetics and map-based cloning approaches.Trends in Plant Science,2003,8:484-491.
[81] Adams M D, Sekelsky J J. From sequence to phenotype: reverse genetics in Drosophila melanogaster. Nat Rev Genet, 2002,3: 189-198.
[82] Orr HT, Chung MY, Banfi S, et al. Expansion of an unstable trinucleotide CAGrepeats in spinocerebellar ataxia type 1. Nat Genet, 1993,4(3):221-226.
[83] Pulst SM, Nechiporuk A, Nechiporuk T, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type2 .Nat Genet 1996,14(3): 269-276.
[84] Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet, 1994, 8(3): 221-228.
[85] Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet, 1997,15(1): 62-69.
[86] Lindblad K, Savontaus ML, Stevanin G, et al. An expanded CAG repeat sequence in spinocerebellar ataxia type 7. Genome Res, 1996,6(10): 965-971.
[87] Nakamura K, Jeong SY, Uchihara T, et al. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet, 2001,10(14): 1441-1448.
[88] Jana NR, Nukina N. Recent advances in understanding the pathogenesis of poly glutamine diseases: involvement of molecular chaperones and ubiquitin- proteasome pathway. J Chem Neuroanat, 2003,26(2):95-101.
[89] Amato.A, Prior.T, W.Barohn, Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology, 1993, 43: 791-794,
[90] Andrew S. E, Goldberg Y. P The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nature Genet, 1993, 4: 398 -403,
[91] Koide R, Ikeuchi T, Onodera O. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet, 1994, 6:9-13,
[92] Robert J. Ferrante, James K. Kubilus.Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's disease Mice. J Neurosci, 2003,23:9418-9427.
[93] Ghazaleh, Sadri-Vakili, Jang-Ho J. Cha .Mechanisms of Disease: histone modific -ations in Huntington's disease. Nature Clinical Practice Neurology 2006,2, 330-338.
[94] Jozsef P. Nemes, Kellie A. Benzow a, Michael D. Koob .The SCA8 transcriptis an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1) Human Molecular Genetics, 2000,9,1543-1551.
[95] Hong Jiang, Ami Mankodi, Maurice S. et al. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons Human Molecular Genetics 2004 13(24):3079-3088
[96] Jonathan M. Houseley , Zongsheng Wang, Graham J. R. Brock Myotonic dystrophy associated expanded CUG repeat muscleblind positive ribonuclear foci are not toxic to Drosophila Human Molecular Genetics 2005 14(6):873-883
[97] McBride S M, Choi C H, Wang Y, et al. Pharmacological rescue of s ynapticplasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron, 2005,45(5): 753-764.
[98] Jin P, Zarnescu D C, Zhang F P, et al. RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila Mechanisms of Disease.Neuron, 2003, 39(5): 739-747.
[99] Mark P. Mattson. Pathways towards and away from Alzheimer's disease Nature.2004,430(5): 631-9
[100] Yoo-Hun Suh and Frederic Checler Amyloid Precursor Protein, Presenilins, and a-Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's disease Pharmacol. Rev., Sep 2002; 54: 469.
[101] Dennis J. Selkoe Alzheimer's Disease: Genes, Proteins, and Therapy Physiol Rev, Apr 2001; 81: 741.
[102] Michael Paul Murphy, et al.Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production Nat Med, 2005, 11(5): 545-50
[103] Igor Klyubin, Dominic M Walsh etc. Amyloid Pprotein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo. Nat Med, 2005, 11(5): 556-613
[104] Peter J Nestor, Philip Scheltens etc. Advances in the early detection of Alzheimer's disease. Nat Neurosci, 2004, July: S34-S41
[105] James P Cleary, Dominic M Walsh etc. Natural oligomers of the amyloid-βprotein specifically disrupt cognitive function Nat Med 2005, 8(1): 79-84
[106] Craig A. Micchelli, William P. Esler, W. et al.g-Secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila FASEB J, Nov 2002; 10.1096.
[107] LQ Luo, LE Martin-Morris, and K White. Identification, secretion, and neural expression of APPL, a Drosophila protein similar to human amyloid protein precursorJ. Neurosci. Dec 1990; 10: 3849.
[108] Koichi Iijima, Hsin-Ping Liu, Ann-Shyn Chiang, et al. Hearn Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila: A potential model for Alzheimer's disease PNAS, 2004; 101: 6623 - 6628.
[109] Greeve, I., Kretzschmar, D., Tschape, et al.Age-dependent neurodegen- eration and Alzheimer-amyloid plaque formation in transgenic Drosophila. J. Neurosci. 2004, 24,3899-3906.
[110] De Jonghe, M Cruts, EA Rogaeva, Aberrant splicing in the presenilin-1 intron 4 mutations causes presenile Alzheimer's disease by increased Abeta42 secretion Hum. Mol. Genet, Aug 1999; 8: 1529 -1540.
[111] Anke Fossgreen, Bodo Bruckner, Christian Czech,Transgenic Drosophila exp -ressing human amyloid precursor protein show γ-secretase activity and a blistered-wing phenotype. PNAS,Nov 1998; 95: 13703.
[112] Miquel Vila, Serge Przedborski. Genetic clues to the pathogenesis of Park inson's disease Nat Med, 2004, July: S58-S62
[113] Bonifati V, Oostra BA, Heutink P. Linking DJ-1 to neurodegeneration offers novel insights for understanding the pathogenesis of Parkinson's disease.J Mol Med, 2004, 82:163-174
[114] Abbas N, Lucking CB, Ricard S,et al.A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. Hum Mol Genet, 1999, 8(4):567-574
[115] Hedrich K, Marder K, Harris J,et al.Evaluation of 50 probands with early -onset Parkinson's disease for Parkin mutations. Neurology, 2002, 58(8): 1239-1246
[116] West A, Periquet M, Lincoln S, et al.Complex relationship between Parkin mutations and Parkinson disease. Am J Med Genet, 2002,114(5):584-591
[117] Hedrich K, Djarmati A, Schafer N, et al.DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease. Neurology, 2004,62(3):389-394.
[118] Bonifati V, Rizzu P, van Baren MJ,et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science, 2003, 299(5604):256- 259.
[119] Hatano Y, Li Y, Sato K, Asakawa S,et al. Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol, 2004, 56:424-427.
[120] J essica C. Greene, Alexander J, Whitworth. Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis Hum. Mol. Genet.2005; 14: 799 -811.
[121] Chen, L. and Feany, M.B. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat. Neurosci 2005, 8, 657-663.
[122] Kitada T,Asakawa S,Hattori N,et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature,1998,392: 605-608
[123] Valente EM, Abou-Sleiman PM.Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1. Science, 2004,304: 1158-1160.
[124] Auluck, P.K., Meulener, M.C., and Bonini, N.M. Mechanisms of suppression of {alpha}-synuclein neurotoxicity by geldanamycin in Drosophila. J. Biol. Chem 2005,280,2873-2878.
[125] Auluck, P.K., Chan, H.Y., Trojanowski, et al. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 2002, 295,865-868.
[126] Klucken.J, Shin. Y, Masliah, et al. Hsp70 Reduces alpha-Synuclein Aggregation and Toxicity. J. Biol. Chem. 2004 , 279, 25497-25502.
[127] Yakov Pesah, Tuan Pham, Heather Burgess, et al.Drosophila parkin mutants have decreased mass and cell size and increased sensitive -ity to oxygen radical stress Development, 2004, 131:2183-2194.
[128] Sang TK, Chang HY, Lawless GM .Drosophila model of mutant human parkin -induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine. J Neurosci, 2007 27:981-92.
[129] Ira E. Clark, Mark W. Dodson, Changan Jiang et al.Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin . Nature,2006 ,441:1162-1166
[130] Yufeng Yang, Stephan Gehrke, Yuzuru Imai et al.Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pinkl is rescued by Parkin .PNAS, Jul 2006; 103: 10793 10798.
[131] Fiona M. Menzies Sarat C. Yenisetti and Kyung-Tai Min et al. Roles of b Drosophila DJ-1 in Survival of Dopaminergic Neurons and Oxidative Stress.Current biology 2005, 6:1578-1582.
[132] Marc C. Meulener, Kexiang Xu, Leonor .Thomson et al. Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. PNAS, 2006,103:12517-12522.
[133] Melissa Lee Phillips.Parkinson Disease: PD Gene and Oxidative StressEnviron Health Perspect. 2006,114: A96.