帕金森病相关蛋白Parkin对自噬调节的研究
摘要
帕金森病(Parkinson's Disease, PD),是一种极为常见的神经退行性疾病,其发病率仅次于阿尔兹海默症(AD),在临床上表现为一系列运动障碍,如静止性震颤、肌肉僵直、姿势反射障碍以及运动迟缓等。帕金森病的发病率和年龄显著正相关,在65岁以上人群发病率约为1%,但是在85岁以上人群发病率激增至3%左右。帕金森病的主要病理特征有两点,一是中脑黑质多巴胺能神经元的选择性死亡,二是在存活的神经元中路易小体(Lewy body)和路易神经突的形成。帕金森病多为散发病例,仅有10-15%的帕金森病属于家族遗传型帕金森病。帕金森病的病因尚不明确,但是环境以及遗传因素被认为是主要诱因。最近,陆续有一些帕金森病致病基因被鉴定出和家族型帕金森病相关,这些基因的突变或者缺失会导致其编码的蛋白质功能异常从而诱导发病。
常染色体隐性遗传的青少年型帕金森病(AR-JP)是一种最为常见的家族型帕金森病,其特点是发病年龄较早,通常在40岁前发病。此病是由于parkin基因的突变而导致的。在所有的早发家族遗传型帕金森病人里有接近50%的病人是由于parkin突变导致的；而且在所有的早发型的散发帕金森病病人中,有15%的病人同样是由于parkin突变导致的。Parkin,又名PARK2,它是一个泛素蛋白酶体系统中的泛素连接酶(E3),其主要功能是在泛素激活酶(E1)和泛素结合酶(E2)的帮助下,识别特定的蛋白底物,通过泛素-蛋白酶体促进该蛋白降解。所以,对于parkin特定底物的寻找一直是帕金森病研究中的一个重点。近来,parkin也被报道可以通过行使其E3连接酶功能对特定底物蛋白的进行泛素化修饰而调控底物蛋白的下游功能,parkin的这一新发现被认为可能是帕金森病病因之一
细胞内的蛋白质降解途径主要有俩种：即上文所提的泛素-蛋白酶体(ubiquitin-proteasom system)途径和细胞自噬(autophagy)途径,他们各自的降解终端分别是蛋白酶体和溶酶体。如果细胞的自噬降解途径发生紊乱,就会诱发神经退行性疾病以及未成熟的神经元的死亡,最近的研究更是直接证明自噬在帕金森病的发病过程中起重要作用。有趣的是,帕金森病相关基因parkin被报道在线粒体损伤剂CCCP处理下可以诱发自噬以清除受损线粒体；并且在parkin敲除鼠模型中,已经发现了自噬的标志蛋白LC3-Ⅱ型蛋白的上调,这些都揭示了parkin与自噬存在联系。但是到目前为止,parkin的功能及其在帕金森病发病过程它与自噬的关系仍不清楚。Parkin及其发病相关突变体与帕金森病的发病过程以及自噬的关系是我们的研究重点。
本文中,我们通过体外以及体内的蛋白结合实验发现,parkin可以特异性的通过其蛋白结构C端的RING1-IBR-RING2吉构与抗凋亡蛋白Bcl-2结合,而不与Bax或者Bcl-xl这俩个Bcl-2家族蛋白结合。进一步研究发现parkin可以通过行使其E3连接酶功能,单泛素化修饰Bcl-2来延长其半衰期,从而上调Bcl-2蛋白含量。所增加的Bcl-2可以结合更多自噬相关蛋白Beclin 1,形成稳定的复合体而抑制自噬,而parkin的发病相关的E3活性受损突变体则丧失了此功能。
本研究提示了parkin在细胞自噬的调控过程中起了重要作用,为更进一步了解parkin的对细胞保护机制,以及帕金森病的分子病理机制提供了新思路。
Parkinson's disease (PD) is the second most common neurodegenerative disorders after Alzheimer's disease and is characterized by a distinct set of motor symptoms, including tremor, muscle rigidity, postural instability and bradykinesia. Aging is the most risk factor in pathogenesis of PD which is estimated to affect approximately 1% of the population at 65 years and increased to 3% at 85. PD is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and by the presence of Lewy bodies (LBs) and Lewy neurites in living neurons. Most of PD patients appear to be sporadic and just approximately 10-15% of PD patients are heriatable PD. Although the cause of PD is poorly understood, there is evidence that both environmental factors and genetic factors contribute to its development. Recently, several genes have been reported to be associated with the pathogenesis of familial forms of PD. Mutations or deletions of these genes leading to dysfunction of proteins are contributed to pathogenesis of PD.
Autosomal recessive juvenile-onset parkinsonism (AR-JP) is a common familial forms of PD, and one notable distinct feature is early-onset before 40 years old. Mutations in the parkin gene have been reported to cause AR-JP. It has been shown that mutations in parkin account for nearly 50% of patients with the early-onset familial PD cases and more than 15% of sporadic PD cases with early onset. Parkin, also named PARK2, is an E3 ubiquitin ligase in ubiquitin-proteasome system (UPS). It works with El buiqui tin-activating enzyme and E2 ubiqui tin-conjugating enzyme to recognize specialy target proteins and enhances their degradation via UPS. So, searching for the new specific substrate of parkin is a hot spot in PD research. Recently, parkin has been reported to ubiquitinate particular protein substrate via its E3 ubiquitin ligase activity to change the substrate to degradation-independent role, and this may be important for molecular pathogenesis of parkin-linked PD.
The ecukaryotic cells have two main protein degradation pathways:the ubiquitin-proteosome pathway and the autophagy-lysosome pathway. Previous studies have shown that the selective ablation of autophagy gene could directly cause neurodegenerative disease. An early report shows that autophagy is important for pathogenesis of PD. These results suggest that autophagy is associated with PD and neurodegeneration. A recent study indicates that in the neuronal cultures of midbrain from parkin null mice, markers of autophagy, such as LC3-Ⅱ/Ⅰ, are increased suggesting that knockout of parkin may induce autophagy. However, the links among parkin, autophagy and PD is still not clear. So, in this study, we focus on the relationship between parkin and autophagy.
We report here that Bcl-2 is a novel substrate for the E3 ubiquitin ligase parkin. Parkin directly interactes with Bcl-2 specifically through its RING1-IBR-RING2 domain in C-terminus and mediates the mono-ubiquitination of Bcl-2. The mono-ubiquitination of Bcl-2 by parkin alters Bcl-2 turnover to increase its protein level. The increased Bcl-2 could bind more Beclin 1 to inhibit autophagy. The PD-linked mutant forms of parkin whose E3 ligase activity are selectively impaired, fail to regulate the mono-ubiquitination of Bcl-2.
These results identify parkin as a novel regulator of autophagy through mono-ubiquitinating Bcl-2 and suggest a new way to understand the protect effects of parkin.
常染色体隐性遗传的青少年型帕金森病(AR-JP)是一种最为常见的家族型帕金森病,其特点是发病年龄较早,通常在40岁前发病。此病是由于parkin基因的突变而导致的。在所有的早发家族遗传型帕金森病人里有接近50%的病人是由于parkin突变导致的；而且在所有的早发型的散发帕金森病病人中,有15%的病人同样是由于parkin突变导致的。Parkin,又名PARK2,它是一个泛素蛋白酶体系统中的泛素连接酶(E3),其主要功能是在泛素激活酶(E1)和泛素结合酶(E2)的帮助下,识别特定的蛋白底物,通过泛素-蛋白酶体促进该蛋白降解。所以,对于parkin特定底物的寻找一直是帕金森病研究中的一个重点。近来,parkin也被报道可以通过行使其E3连接酶功能对特定底物蛋白的进行泛素化修饰而调控底物蛋白的下游功能,parkin的这一新发现被认为可能是帕金森病病因之一
细胞内的蛋白质降解途径主要有俩种：即上文所提的泛素-蛋白酶体(ubiquitin-proteasom system)途径和细胞自噬(autophagy)途径,他们各自的降解终端分别是蛋白酶体和溶酶体。如果细胞的自噬降解途径发生紊乱,就会诱发神经退行性疾病以及未成熟的神经元的死亡,最近的研究更是直接证明自噬在帕金森病的发病过程中起重要作用。有趣的是,帕金森病相关基因parkin被报道在线粒体损伤剂CCCP处理下可以诱发自噬以清除受损线粒体；并且在parkin敲除鼠模型中,已经发现了自噬的标志蛋白LC3-Ⅱ型蛋白的上调,这些都揭示了parkin与自噬存在联系。但是到目前为止,parkin的功能及其在帕金森病发病过程它与自噬的关系仍不清楚。Parkin及其发病相关突变体与帕金森病的发病过程以及自噬的关系是我们的研究重点。
本文中,我们通过体外以及体内的蛋白结合实验发现,parkin可以特异性的通过其蛋白结构C端的RING1-IBR-RING2吉构与抗凋亡蛋白Bcl-2结合,而不与Bax或者Bcl-xl这俩个Bcl-2家族蛋白结合。进一步研究发现parkin可以通过行使其E3连接酶功能,单泛素化修饰Bcl-2来延长其半衰期,从而上调Bcl-2蛋白含量。所增加的Bcl-2可以结合更多自噬相关蛋白Beclin 1,形成稳定的复合体而抑制自噬,而parkin的发病相关的E3活性受损突变体则丧失了此功能。
本研究提示了parkin在细胞自噬的调控过程中起了重要作用,为更进一步了解parkin的对细胞保护机制,以及帕金森病的分子病理机制提供了新思路。
Parkinson's disease (PD) is the second most common neurodegenerative disorders after Alzheimer's disease and is characterized by a distinct set of motor symptoms, including tremor, muscle rigidity, postural instability and bradykinesia. Aging is the most risk factor in pathogenesis of PD which is estimated to affect approximately 1% of the population at 65 years and increased to 3% at 85. PD is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and by the presence of Lewy bodies (LBs) and Lewy neurites in living neurons. Most of PD patients appear to be sporadic and just approximately 10-15% of PD patients are heriatable PD. Although the cause of PD is poorly understood, there is evidence that both environmental factors and genetic factors contribute to its development. Recently, several genes have been reported to be associated with the pathogenesis of familial forms of PD. Mutations or deletions of these genes leading to dysfunction of proteins are contributed to pathogenesis of PD.
Autosomal recessive juvenile-onset parkinsonism (AR-JP) is a common familial forms of PD, and one notable distinct feature is early-onset before 40 years old. Mutations in the parkin gene have been reported to cause AR-JP. It has been shown that mutations in parkin account for nearly 50% of patients with the early-onset familial PD cases and more than 15% of sporadic PD cases with early onset. Parkin, also named PARK2, is an E3 ubiquitin ligase in ubiquitin-proteasome system (UPS). It works with El buiqui tin-activating enzyme and E2 ubiqui tin-conjugating enzyme to recognize specialy target proteins and enhances their degradation via UPS. So, searching for the new specific substrate of parkin is a hot spot in PD research. Recently, parkin has been reported to ubiquitinate particular protein substrate via its E3 ubiquitin ligase activity to change the substrate to degradation-independent role, and this may be important for molecular pathogenesis of parkin-linked PD.
The ecukaryotic cells have two main protein degradation pathways:the ubiquitin-proteosome pathway and the autophagy-lysosome pathway. Previous studies have shown that the selective ablation of autophagy gene could directly cause neurodegenerative disease. An early report shows that autophagy is important for pathogenesis of PD. These results suggest that autophagy is associated with PD and neurodegeneration. A recent study indicates that in the neuronal cultures of midbrain from parkin null mice, markers of autophagy, such as LC3-Ⅱ/Ⅰ, are increased suggesting that knockout of parkin may induce autophagy. However, the links among parkin, autophagy and PD is still not clear. So, in this study, we focus on the relationship between parkin and autophagy.
We report here that Bcl-2 is a novel substrate for the E3 ubiquitin ligase parkin. Parkin directly interactes with Bcl-2 specifically through its RING1-IBR-RING2 domain in C-terminus and mediates the mono-ubiquitination of Bcl-2. The mono-ubiquitination of Bcl-2 by parkin alters Bcl-2 turnover to increase its protein level. The increased Bcl-2 could bind more Beclin 1 to inhibit autophagy. The PD-linked mutant forms of parkin whose E3 ligase activity are selectively impaired, fail to regulate the mono-ubiquitination of Bcl-2.
These results identify parkin as a novel regulator of autophagy through mono-ubiquitinating Bcl-2 and suggest a new way to understand the protect effects of parkin.
引文
Abbas, N., C. B. Lucking, et al. (1999). "A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease." Hum Mol Genet 8(4):567-74.
Baldereschi, M., A. Di Carlo, et al. (2000). "Parkinson's disease and parkinsonism in a longitudinal study:two-fold higher incidence in men. ILSA Working Group. Italian Longitudinal Study on Aging." Neurology 55(9):1358-63.
Berger, A. K., G. P. Cortese, et al. (2009). "Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release." Hum Mol Genet 18(22):4317-28.
Betarbet, R., T. B. Sherer, et al. (2000). "Chronic systemic pesticide exposure reproduces features of Parkinson's disease." Nat Neurosci 3(12):1301-6.
Bower, J. H., D. M. Maraganore, et al. (2000). "Influence of strict, intermediate, and broad diagnostic criteria on the age-and sex-specific incidence of Parkinson's disease." Mov Disord 15(5): 819-25.
Brunelle, J. K. and A. Letai (2009). "Control of mitochondrial apoptosis by the Bcl-2 family." J Cell Sci 122(Pt 4):437-41.
Casarejos, M. J., R. M. Solano, et al. (2009). "Parkin deficiency increases the resistance of midbrain neurons and glia to mild proteasome inhibition:the role of autophagy and glutathione homeostasis." J Neurochem 110(5):1523-37.
Choi, P., H. Snyder, et al. (2003). "SEPT5_v2 is a parkin-binding protein." Brain Res Mol Brain Res 117(2):179-89.
Chung, K. K., Y. Zhang, et al. (2001). "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1:implications for Lewy-body formation in Parkinson disease." Nat Med 7(10): 1144-50.
Corti, O., C. Hampe, et al. (2003). "The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate:linking protein biosynthesis and neurodegeneration." Hum Mol Genet 12(12): 1427-37.
Cuervo, A. M., L. Stefanis, et al. (2004). "Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy." Science 305(5688):1292-5.
da Costa, C. A., C. Sunyach, et al. (2009). "Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease." Nat Cell Biol 11(11):1370-5.
Darios, F., O. Corti, et al. (2003). "Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death." Hum Mol Genet 12(5):517-26.
Denison, S. R., F. Wang, et al. (2003). "Alterations in the common fragile site gene Parkin in ovarian and other cancers." Oncogene 22(51):8370-8.
Duncan, C., T. Papanikolaou, et al. "Autophagy:polyQ toxic fragment turnover." Autophagy 6(2): 312-4.
Fahn, S. and D. Sulzer (2004). "Neurodegeneration and neuroprotection in Parkinson disease." NeuroRx 1(1):139-54.
Gasser, T. (2007). "Update on the genetics of Parkinson's disease." Mov Disord 22 Suppl 17:S343-50.
Geisler, S., K. M. Holmstrom, et al. "PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1." Nat Cell Biol 12(2):119-31.
Guilarte, T. R., M. K. Chen, et al. (2006). "Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates." Exp Neurol 202(2):381-90.
Hara, T., K. Nakamura, et al. (2006). "Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice." Nature 441(7095):885-9.
Huynh, D. P., D. R. Scoles, et al. (2003). "The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI." Hum Mol Genet 12(20): 2587-97.
Imai, Y., M. Soda, et al. (2001). "An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin." Cell 105(7):891-902.
Imai, Y., M. Soda, et al. (2000). "Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity." J Biol Chem 275(46):35661-4.
Irrcher, I. and D. S. Park (2009). "Parkinson's disease:to live or die by autophagy." Sci Signal 2(65): pe21.
Jiang, H., Y. Ren, et al. (2004). "Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis." Hum Mol Genet 13(16):1745-54.
Kabeya, Y., N. Mizushima, et al. (2000). "LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing." EMBO J 19(21):5720-8.
Klionsky, D. J. (2007). "Autophagy:from phenomenology to molecular understanding in less than a decade." Nat Rev Mol Cell Biol 8(11):931-7.
Ko, H. S., S. W. Kim, et al. (2006). "Identification of far upstream element-binding protein-1 as an authentic Parkin substrate." J Biol Chem 281(24):16193-6.
Ko, H. S., R. von Coelln, et al. (2005). "Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death." J Neurosci 25(35):7968-78.
Komatsu, M., S. Waguri, et al. (2006). "Loss of autophagy in the central nervous system causes neurodegeneration in mice." Nature 441(7095):880-4.
Kuroda, Y., T. Mitsui, et al. (2006). "Parkin enhances mitochondrial biogenesis in proliferating cells.1 Hum Mol Genet 15(6):883-95.
Levine, B. and G. Kroemer (2008). "Autophagy in the pathogenesis of disease." Cell 132(1):27-42.
Lim, K. L., K. C. Chew, et al. (2005). "Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1:implications for Lewy body formation." J Neurosci 25(8): 2002-9.
Lucking, C. B., A. Durr, et al. (2000). "Association between early-onset Parkinson's disease and mutations in the parkin gene." N Engl J Med 342(21):1560-7.
Marino, G. and C. Lopez-Otin (2004). "Autophagy:molecular mechanisms, physiological functions and relevance in human pathology." Cell Mol Life Sci 61(12):1439-54.
Maruyama, M., T. Ikeuchi, et al. (2000). "Novel mutations, pseudo-dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism." Ann Neurol 48(2): 245-50.
Mizushima, N. (2007). "Autophagy:process and function." Genes Dev 21(22):2861-73.
Mizushima, N., A. Yamamoto, et al. (2004). "In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker." Mol Biol Cell 15(3):1101-11.
Moore, D. J., A. B. West, et al. (2005). "Molecular pathophysiology of Parkinson's disease." Annu Rev Neurosci 28:57-87.
Moore, D. J., A. B. West, et al. (2008). "Parkin mediates the degradation-independent ubiquitination of Hsp70."J Neurochem 105(5):1806-19.
Narendra, D., A. Tanaka, et al. (2008). "Parkin is recruited selectively to impaired mitochondria and promotes their autophagy." J Cell Biol 183(5):795-803.
Nedelsky, N. B., P. K. Todd, et al. (2008). "Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection." Biochim Biophys Acta 1782(12):691-9.
Nichols, W. C., N. Pankratz, et al. (2002). "Linkage stratification and mutation analysis at the Parkin locus identifies mutation positive Parkinson's disease families." J Med Genet 39(7):489-92.
Offen, D., I. Ziv, et al. (1997). "Dopamine-induced apoptosis is inhibited in PC12 cells expressing Bcl-2." Cell Mol Neurobiol 17(3):289-304.
Pattingre, S., A. Tassa, et al. (2005). "Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy." Cell 122(6):927-39.
Pawlyk, A. C., B. I. Giasson, et al. (2003). "Novel monoclonal antibodies demonstrate biochemical variation of brain parkin with age." J Biol Chem 278(48):48120-8.
Periquet, M., M. Latouche, et al. (2003). "Parkin mutations are frequent in patients with isolated early-onset parkinsonism." Brain 126(Pt 6):1271-8.
Periquet, M., C. Lucking, et al. (2001). "Origin of the mutations in the parkin gene in Europe:exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects." Am J Hum Genet 68(3):617 26.
Pickart, C. M. (2001). "Mechanisms underlying ubiquitination." Annu Rev Biochem 70:503-33.
Ren, Y., J. Zhao, et al. (2003). "Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation." J Neurosci 23(8):3316-24.
Sakata, E., Y. Yamaguchi, et al. (2003). "Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain." EMBO Rep 4(3):301-6.
Scott, W. K., M. A. Nance, et al. (2001). "Complete genomic screen in Parkinson disease:evidence for multiple genes." JAMA 286(18):2239-44.
Shimura, H., N. Hattori, et al. (2000). "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase." Nat Genet 25(3):302-5.
Shimura, H., N. Hattori, et al. (1999). "Immunohistochemical and subcellular localization of Parkin protein:absence of protein in autosomal recessive juvenile parkinsonism patients." Ann Neurol 45(5):668-72.
Takai, N., H. Nakanishi, et al. (1998). "Involvement of caspase-like proteinases in apoptosis of neuronal PC 12 cells and primary cultured microglia induced by 6-hydroxydopamine." J Neurosci Res 54(2):214-22.
Thomas, B. and M. F. Beal (2007). "Parkinson's disease." Hum Mol Genet 16 Spec No.2:R183-94.
Vercammen, L., A. Van der Perren, et al. (2006). "Parkin protects against neurotoxicity in the 6-hydroxydopamine rat model for Parkinson's disease." Mol Ther 14(5):716-23.
West, A. B. and N. T. Maidment (2004). "Genetics of parkin-linked disease." Hum Genet 114(4): 327-36.
Williams, A., L. Jahreiss, et al. (2006). "Aggregate-prone proteins are cleared from the cytosol by autophagy:therapeutic implications." Curr Top Dev Biol 76:89-101.
Yang, E., J. Zha, et al. (1995). "Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death." Cell 80(2):285-91.
Yang, J., X. Liu, et al. (1997). "Prevention of apoptosis by Bcl-2:release of cytochrome c from mitochondria blocked." Science 275(5303):1129-32.
Zhang, Y., J. Gao, et al. (2000). "Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1." Proc Natl Acad Sci U S A 97(24):13354-9.
Baldereschi, M., A. Di Carlo, et al. (2000). "Parkinson's disease and parkinsonism in a longitudinal study:two-fold higher incidence in men. ILSA Working Group. Italian Longitudinal Study on Aging." Neurology 55(9):1358-63.
Berger, A. K., G. P. Cortese, et al. (2009). "Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release." Hum Mol Genet 18(22):4317-28.
Betarbet, R., T. B. Sherer, et al. (2000). "Chronic systemic pesticide exposure reproduces features of Parkinson's disease." Nat Neurosci 3(12):1301-6.
Bower, J. H., D. M. Maraganore, et al. (2000). "Influence of strict, intermediate, and broad diagnostic criteria on the age-and sex-specific incidence of Parkinson's disease." Mov Disord 15(5): 819-25.
Brunelle, J. K. and A. Letai (2009). "Control of mitochondrial apoptosis by the Bcl-2 family." J Cell Sci 122(Pt 4):437-41.
Casarejos, M. J., R. M. Solano, et al. (2009). "Parkin deficiency increases the resistance of midbrain neurons and glia to mild proteasome inhibition:the role of autophagy and glutathione homeostasis." J Neurochem 110(5):1523-37.
Choi, P., H. Snyder, et al. (2003). "SEPT5_v2 is a parkin-binding protein." Brain Res Mol Brain Res 117(2):179-89.
Chung, K. K., Y. Zhang, et al. (2001). "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1:implications for Lewy-body formation in Parkinson disease." Nat Med 7(10): 1144-50.
Corti, O., C. Hampe, et al. (2003). "The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate:linking protein biosynthesis and neurodegeneration." Hum Mol Genet 12(12): 1427-37.
Cuervo, A. M., L. Stefanis, et al. (2004). "Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy." Science 305(5688):1292-5.
da Costa, C. A., C. Sunyach, et al. (2009). "Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease." Nat Cell Biol 11(11):1370-5.
Darios, F., O. Corti, et al. (2003). "Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death." Hum Mol Genet 12(5):517-26.
Denison, S. R., F. Wang, et al. (2003). "Alterations in the common fragile site gene Parkin in ovarian and other cancers." Oncogene 22(51):8370-8.
Duncan, C., T. Papanikolaou, et al. "Autophagy:polyQ toxic fragment turnover." Autophagy 6(2): 312-4.
Fahn, S. and D. Sulzer (2004). "Neurodegeneration and neuroprotection in Parkinson disease." NeuroRx 1(1):139-54.
Gasser, T. (2007). "Update on the genetics of Parkinson's disease." Mov Disord 22 Suppl 17:S343-50.
Geisler, S., K. M. Holmstrom, et al. "PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1." Nat Cell Biol 12(2):119-31.
Guilarte, T. R., M. K. Chen, et al. (2006). "Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates." Exp Neurol 202(2):381-90.
Hara, T., K. Nakamura, et al. (2006). "Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice." Nature 441(7095):885-9.
Huynh, D. P., D. R. Scoles, et al. (2003). "The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI." Hum Mol Genet 12(20): 2587-97.
Imai, Y., M. Soda, et al. (2001). "An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin." Cell 105(7):891-902.
Imai, Y., M. Soda, et al. (2000). "Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity." J Biol Chem 275(46):35661-4.
Irrcher, I. and D. S. Park (2009). "Parkinson's disease:to live or die by autophagy." Sci Signal 2(65): pe21.
Jiang, H., Y. Ren, et al. (2004). "Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis." Hum Mol Genet 13(16):1745-54.
Kabeya, Y., N. Mizushima, et al. (2000). "LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing." EMBO J 19(21):5720-8.
Klionsky, D. J. (2007). "Autophagy:from phenomenology to molecular understanding in less than a decade." Nat Rev Mol Cell Biol 8(11):931-7.
Ko, H. S., S. W. Kim, et al. (2006). "Identification of far upstream element-binding protein-1 as an authentic Parkin substrate." J Biol Chem 281(24):16193-6.
Ko, H. S., R. von Coelln, et al. (2005). "Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death." J Neurosci 25(35):7968-78.
Komatsu, M., S. Waguri, et al. (2006). "Loss of autophagy in the central nervous system causes neurodegeneration in mice." Nature 441(7095):880-4.
Kuroda, Y., T. Mitsui, et al. (2006). "Parkin enhances mitochondrial biogenesis in proliferating cells.1 Hum Mol Genet 15(6):883-95.
Levine, B. and G. Kroemer (2008). "Autophagy in the pathogenesis of disease." Cell 132(1):27-42.
Lim, K. L., K. C. Chew, et al. (2005). "Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1:implications for Lewy body formation." J Neurosci 25(8): 2002-9.
Lucking, C. B., A. Durr, et al. (2000). "Association between early-onset Parkinson's disease and mutations in the parkin gene." N Engl J Med 342(21):1560-7.
Marino, G. and C. Lopez-Otin (2004). "Autophagy:molecular mechanisms, physiological functions and relevance in human pathology." Cell Mol Life Sci 61(12):1439-54.
Maruyama, M., T. Ikeuchi, et al. (2000). "Novel mutations, pseudo-dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism." Ann Neurol 48(2): 245-50.
Mizushima, N. (2007). "Autophagy:process and function." Genes Dev 21(22):2861-73.
Mizushima, N., A. Yamamoto, et al. (2004). "In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker." Mol Biol Cell 15(3):1101-11.
Moore, D. J., A. B. West, et al. (2005). "Molecular pathophysiology of Parkinson's disease." Annu Rev Neurosci 28:57-87.
Moore, D. J., A. B. West, et al. (2008). "Parkin mediates the degradation-independent ubiquitination of Hsp70."J Neurochem 105(5):1806-19.
Narendra, D., A. Tanaka, et al. (2008). "Parkin is recruited selectively to impaired mitochondria and promotes their autophagy." J Cell Biol 183(5):795-803.
Nedelsky, N. B., P. K. Todd, et al. (2008). "Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection." Biochim Biophys Acta 1782(12):691-9.
Nichols, W. C., N. Pankratz, et al. (2002). "Linkage stratification and mutation analysis at the Parkin locus identifies mutation positive Parkinson's disease families." J Med Genet 39(7):489-92.
Offen, D., I. Ziv, et al. (1997). "Dopamine-induced apoptosis is inhibited in PC12 cells expressing Bcl-2." Cell Mol Neurobiol 17(3):289-304.
Pattingre, S., A. Tassa, et al. (2005). "Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy." Cell 122(6):927-39.
Pawlyk, A. C., B. I. Giasson, et al. (2003). "Novel monoclonal antibodies demonstrate biochemical variation of brain parkin with age." J Biol Chem 278(48):48120-8.
Periquet, M., M. Latouche, et al. (2003). "Parkin mutations are frequent in patients with isolated early-onset parkinsonism." Brain 126(Pt 6):1271-8.
Periquet, M., C. Lucking, et al. (2001). "Origin of the mutations in the parkin gene in Europe:exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects." Am J Hum Genet 68(3):617 26.
Pickart, C. M. (2001). "Mechanisms underlying ubiquitination." Annu Rev Biochem 70:503-33.
Ren, Y., J. Zhao, et al. (2003). "Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation." J Neurosci 23(8):3316-24.
Sakata, E., Y. Yamaguchi, et al. (2003). "Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain." EMBO Rep 4(3):301-6.
Scott, W. K., M. A. Nance, et al. (2001). "Complete genomic screen in Parkinson disease:evidence for multiple genes." JAMA 286(18):2239-44.
Shimura, H., N. Hattori, et al. (2000). "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase." Nat Genet 25(3):302-5.
Shimura, H., N. Hattori, et al. (1999). "Immunohistochemical and subcellular localization of Parkin protein:absence of protein in autosomal recessive juvenile parkinsonism patients." Ann Neurol 45(5):668-72.
Takai, N., H. Nakanishi, et al. (1998). "Involvement of caspase-like proteinases in apoptosis of neuronal PC 12 cells and primary cultured microglia induced by 6-hydroxydopamine." J Neurosci Res 54(2):214-22.
Thomas, B. and M. F. Beal (2007). "Parkinson's disease." Hum Mol Genet 16 Spec No.2:R183-94.
Vercammen, L., A. Van der Perren, et al. (2006). "Parkin protects against neurotoxicity in the 6-hydroxydopamine rat model for Parkinson's disease." Mol Ther 14(5):716-23.
West, A. B. and N. T. Maidment (2004). "Genetics of parkin-linked disease." Hum Genet 114(4): 327-36.
Williams, A., L. Jahreiss, et al. (2006). "Aggregate-prone proteins are cleared from the cytosol by autophagy:therapeutic implications." Curr Top Dev Biol 76:89-101.
Yang, E., J. Zha, et al. (1995). "Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death." Cell 80(2):285-91.
Yang, J., X. Liu, et al. (1997). "Prevention of apoptosis by Bcl-2:release of cytochrome c from mitochondria blocked." Science 275(5303):1129-32.
Zhang, Y., J. Gao, et al. (2000). "Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1." Proc Natl Acad Sci U S A 97(24):13354-9.