GCDH沉默和赖氨酸过量对纹状体神经元的神经毒性作用及机制研究
|
摘要
第一部分赖氨酸致原代大鼠纹状体神经元神经毒性的体外研究
目的分离培养高纯度的原代大鼠纹状体神经元,探讨赖氨酸对体外培养纹状体神经元的神经毒性作用。
方法分离出生24h内SD乳鼠的纹状体,应用胰酶消化、无血清培养基培养法培养纹状体神经元。利用微管相关蛋白(microtubule-associated protein MAP2)染色免疫荧光及流式细胞方法鉴定神经元纯度。不同浓度的赖氨酸(0、5、10、15、20mmol/L)干预神经元24h后,MTT法测定细胞活性,探讨不同浓度赖氨酸对原代纹状体神经元的神经毒性作用。
结果MAP2免疫荧光法显示培养细胞神经元纯度为92.4±1.6%,MAP2染色流式细胞计数显示神经元纯度为94.3±2.5%。MTT结果显示小于10mmol/L赖氨酸干预24h对神经元存活无影响。15mmol/L赖氨酸干预24h神经元存活率为84.63%,20mmol/L赖氨酸干预24h神经元存活率降为45.60%。
结论胰酶消化无血清培养基培养法可成功培养高纯度的大鼠纹状体神经元。赖氨酸干预24h,浓度不超过10mmol/L时对神经元无毒性,浓度达到15mmol/L以上时,赖氨酸神经毒性呈浓度依赖型,浓度越高,神经元存活率越低。结合正常人类给予高赖氨酸饮食并不致病考虑,后续实验选取5mmol/L、10mmol/L赖氨酸干预GCDH基因沉默神经元,探讨神经损伤机制。
第二部分慢病毒介导的GCDH基因沉默和赖氨酸过量摄取对纹状体神经元的神经毒性作用
目的利用慢病毒载体携带shRNA转染纹状体神经元细胞内并稳定表达,靶向抑制GCDH基因表达,大量赖氨酸饲养模拟细胞高代谢状态,探讨大量赖氨酸对GCDH基因沉默神经元的神经毒性作用。
方法利用已知的靶向沉默大鼠GCDH基因的siRNA序列构建慢病毒载体,并利用病毒载体携带的绿色荧光蛋白(green fluorescent protein, GFP)的表达确定最佳感染复数。Real-time PCR和Western blot测定GCDH基因沉默效率。MTT检测赖氨酸对GCDH基因沉默神经元细胞活性影响。Hoechest33342检测细胞核形态变化。
结果慢病毒携带shRNA载体成功转染原代大鼠纹状体神经元,转染效率高达96.5%。该载体能有效抑制GCDH基因表达,蛋白表达下降80.78%。慢病毒介导的GCDH基因沉默降低纹状体神经元细胞活性至68.62%,5mmol/L、10mmol/L赖氨酸饲养则进一步降低细胞活性,且呈浓度依赖性。阴性对照组空载体慢病毒对神经元活性无影响。5mmol/L赖氨酸对阴性对照组神经元细胞活性无影响,但10mmol/L赖氨酸降低阴性对照组神经元细胞活性。Hoechest33342染色显示细胞活性降低组神经元的细胞核呈凋亡表现。
结论慢病毒携带shRNA载体能有效且稳定的抑制神经元GCDH基因表达。5mmol/L赖氨酸对正常纹状体神经元活性无影响,对GCDH基因沉默神经元有明显的致凋亡作用。5mmol/L赖氨酸作用于GCDH基因沉默神经元可模拟GA1患儿高代谢状态,成功建立新的GA1研究模型,为研究GA1神经损伤机制提供实验基础。
第三部分赖氨酸对GCDH基因沉默纹状体神经元神经毒性作用的可能机制探讨
目的探讨赖氨酸对GCDH基因沉默纹状体神经元神经毒性作用的可能机制。
方法TMRM (tetramethylrhodamine methyl ester)染色、共聚焦显微镜和流式检测细胞线粒体膜电位变化。Western blot检测各处理组神经元caspase3,8,9蛋白表达情况。在用慢病毒感染神经元之前,先用caspase抑制剂Z-VAD-FMK (benzyloxy-carbonyl-Val-Ala-Asp(OMe)-fluoromethylketone)100μmol/L预孵育1h。然后再用Annexin V-PE/7-AAD流式定量分析各组神经元凋亡情况。
结果TMRM染色、共聚焦显微镜和流式均显示GCDH基因沉默神经元线粒体膜电位明显降低,5mmol/L赖氨酸饲养更进一步促进线粒体膜电位降低。GCDH基因沉默神经元内caspase3,9蛋白表达明显增加,caspase8蛋白表达无明显变化。5mmol/L赖氨酸饲养促进GCDH基因沉默神经元内caspase3,8,9蛋白表达增加。Z-VAD-FMK预处理后,流式显示GCDH基因沉默神经元及赖氨酸饲养GCDH基因沉默神经元的细胞凋亡比例均明显下降。
结论线粒体膜电位变化参与赖氨酸对GCDH基因沉默纹状体神经元神经毒性作用机制,同时该神经毒性是caspase途径依赖型。
Part I The in vitro study of neurotoxicity induced by lysine in primary rat striatal neurons
Objective To culture and identify primary rat striatal neurons. To investigate the neurotoxic effect of lysine on rat striatal neurons in vitro.
Methods Striatum tissues were separated from SD rats born within24h. Trypsin digestion and serum free cultivation method were used to culture primary striatal neurons. The purity of neurons was identified by using immunohistochemical method of neuron specific enolase (NSE), using immunofluorescence and flow cytometry methods of microtubule associated protein (MAP2).24h after the intervention of different concentrations of lysine (0,5,10,15,20mmol/L) with neurons, the cell viability was determined by MTT method. Discussed the neurotoxicity induced by different concentrations of lysine in primary rat striatal neurons.
Results This method cuccessfully cultured rat striatal neurons. MAP2immunofluorescence showed that the purity of neurons was92.4±1.6%. MAP2staining flow cytometry showed that the purity of neurons was94.3±2.5%. NSE immunohistochemistry showed the purity of neurons was96.2±3.3%. The neurotoxicity induced by lysine in primary rat striatal neurons was concentration dependent. After incubated with lysine for24h, the results of MTT showed the concentration less than10mmol/L had no effect on neuron viability,15mmol/L and20mmol/L lysine reduced the viability of neurons to84.63%and45.60%respectively.
Conclusion The rat striatal neurons with high purity were successfully cultured by using trypsin digestion and serum free cultivation method. Lysine intervention for24h, the concentration of not more than10mmol/L had no neurotoxic effect on neurons. When the concentration reached more than15mmol/L, the neurotoxicity was concentration dependent. In view of that high lysine diet does not promote neurotoxicity in normal human, the concentrations of5mmol/L and10mmol/L were used in the following experiments.
Part II The neurotoxicity of targeted suppression of GCDH by lentivirus-mediated shRNA and excessive intake of lysine on rat striatal neurons
Objective To investigate the neurotoxicity induced by excessive lysine in GCDH silencing neurons by using lentivirus-mediated shRNA and excessive intake of lysine.
Methods Lentiviral vector was constructed by using a known siRNA sequence targeted suppression of GCDH gene expression. The appropriate multiplicity of infection was determined by using GFP carried by virus vector. The interference efficiency of lentivirus was determined by using Real-time PCR and Western blotting. The viability of GCDH silencing neurons incubated with lysine or not was determined by using MTT. The nuclear morphological changes in rat neurons were detected by using Hoechst33342staining. The quantity of neural apoptosis was analysed by using Annexin V-PE/7-AAD and flow cytometry.
Results shRNA was transfected into primary rat striatal neurons successfully by using lentiviral vector, and the transfection efficiency was as high as96.5%. The vector can effectively suppressed the GCDH gene expression. The expression of protein was reduced as much as80.78%. The targeted suppression of GCDH by lentivirus-mediated shRNA reduced the neuron viability to68.62%,5mmol/L and10mmol/L lysine enhanced this effect markedly, and the neurotoxicity was concentration dependent. Hoechst33342 staining showed nuclear apoptosis. Annexin V-PE/7-AAD flow quantitative analysis further verified the results of MTT analysis.
Conclusion Lentivirus-mediated shRNA vector suppressed the expression of GCDH gene effectively and stably.5mmol/L lysine had no effect on neuron viability, but induced GCDH silencing neurons apoptosis. GCDH silencing neurons incubated with addition of5mmol/L lysine can simulate the hypermetabolic condition in GA1patients. A novel model of GA1was established.
PartⅢ the mechanism of the neurotoxicity induced by lysine in GCDH silencing neurons was investigated
Objective To investigate the the mechanism of the neurotoxicity induced by lysine in GCDH silencing neurons.
Methods Mitochondrial membrane potential was monitored using TMRM staining, confocal microscope and flow cytometry. The levels of caspase3,8,9, AIF and Hsp70expression were determined by Western bloting.100μmol/L Z-VAD-FMK was added to the medium1h prior to lentiviral infection, and then the quantity of neural apoptosis was analysed by using Annexin V-PE/7-AAD and flow cytometry.
Results TMRM staining, confocal microscope and flow cytometry all showed suppression the expression of GCDH gene significantly decreased the neuron mitochondrial membrane potential, and5mmol/L lysine enhanced this decrease. The protein levels of caspases3and9were significantly upregulated by lentivirus. The combination of lysine and lentivirus intensified the upregulation of caspases3and9. Neither lentivirus nor5mmol/L lysine alone changed the level of caspase8expression, but exposure to both increased the protein level of caspase8. With Z-VAD-FMK pretreatment, the apoptotic cell fraction in cells infected with lentivirus decreased to21.87%in cells not exposed to lysine and41.66%in cells exposed to5mmol/L lysine.
Conclusion Mitochondrial membrane potential changes may be involved in the the mechanism of the neurotoxicity induced by lysine in GCDH silencing neurons. And the neurotoxicity is caspase pathway dependent.
目的分离培养高纯度的原代大鼠纹状体神经元,探讨赖氨酸对体外培养纹状体神经元的神经毒性作用。
方法分离出生24h内SD乳鼠的纹状体,应用胰酶消化、无血清培养基培养法培养纹状体神经元。利用微管相关蛋白(microtubule-associated protein MAP2)染色免疫荧光及流式细胞方法鉴定神经元纯度。不同浓度的赖氨酸(0、5、10、15、20mmol/L)干预神经元24h后,MTT法测定细胞活性,探讨不同浓度赖氨酸对原代纹状体神经元的神经毒性作用。
结果MAP2免疫荧光法显示培养细胞神经元纯度为92.4±1.6%,MAP2染色流式细胞计数显示神经元纯度为94.3±2.5%。MTT结果显示小于10mmol/L赖氨酸干预24h对神经元存活无影响。15mmol/L赖氨酸干预24h神经元存活率为84.63%,20mmol/L赖氨酸干预24h神经元存活率降为45.60%。
结论胰酶消化无血清培养基培养法可成功培养高纯度的大鼠纹状体神经元。赖氨酸干预24h,浓度不超过10mmol/L时对神经元无毒性,浓度达到15mmol/L以上时,赖氨酸神经毒性呈浓度依赖型,浓度越高,神经元存活率越低。结合正常人类给予高赖氨酸饮食并不致病考虑,后续实验选取5mmol/L、10mmol/L赖氨酸干预GCDH基因沉默神经元,探讨神经损伤机制。
第二部分慢病毒介导的GCDH基因沉默和赖氨酸过量摄取对纹状体神经元的神经毒性作用
目的利用慢病毒载体携带shRNA转染纹状体神经元细胞内并稳定表达,靶向抑制GCDH基因表达,大量赖氨酸饲养模拟细胞高代谢状态,探讨大量赖氨酸对GCDH基因沉默神经元的神经毒性作用。
方法利用已知的靶向沉默大鼠GCDH基因的siRNA序列构建慢病毒载体,并利用病毒载体携带的绿色荧光蛋白(green fluorescent protein, GFP)的表达确定最佳感染复数。Real-time PCR和Western blot测定GCDH基因沉默效率。MTT检测赖氨酸对GCDH基因沉默神经元细胞活性影响。Hoechest33342检测细胞核形态变化。
结果慢病毒携带shRNA载体成功转染原代大鼠纹状体神经元,转染效率高达96.5%。该载体能有效抑制GCDH基因表达,蛋白表达下降80.78%。慢病毒介导的GCDH基因沉默降低纹状体神经元细胞活性至68.62%,5mmol/L、10mmol/L赖氨酸饲养则进一步降低细胞活性,且呈浓度依赖性。阴性对照组空载体慢病毒对神经元活性无影响。5mmol/L赖氨酸对阴性对照组神经元细胞活性无影响,但10mmol/L赖氨酸降低阴性对照组神经元细胞活性。Hoechest33342染色显示细胞活性降低组神经元的细胞核呈凋亡表现。
结论慢病毒携带shRNA载体能有效且稳定的抑制神经元GCDH基因表达。5mmol/L赖氨酸对正常纹状体神经元活性无影响,对GCDH基因沉默神经元有明显的致凋亡作用。5mmol/L赖氨酸作用于GCDH基因沉默神经元可模拟GA1患儿高代谢状态,成功建立新的GA1研究模型,为研究GA1神经损伤机制提供实验基础。
第三部分赖氨酸对GCDH基因沉默纹状体神经元神经毒性作用的可能机制探讨
目的探讨赖氨酸对GCDH基因沉默纹状体神经元神经毒性作用的可能机制。
方法TMRM (tetramethylrhodamine methyl ester)染色、共聚焦显微镜和流式检测细胞线粒体膜电位变化。Western blot检测各处理组神经元caspase3,8,9蛋白表达情况。在用慢病毒感染神经元之前,先用caspase抑制剂Z-VAD-FMK (benzyloxy-carbonyl-Val-Ala-Asp(OMe)-fluoromethylketone)100μmol/L预孵育1h。然后再用Annexin V-PE/7-AAD流式定量分析各组神经元凋亡情况。
结果TMRM染色、共聚焦显微镜和流式均显示GCDH基因沉默神经元线粒体膜电位明显降低,5mmol/L赖氨酸饲养更进一步促进线粒体膜电位降低。GCDH基因沉默神经元内caspase3,9蛋白表达明显增加,caspase8蛋白表达无明显变化。5mmol/L赖氨酸饲养促进GCDH基因沉默神经元内caspase3,8,9蛋白表达增加。Z-VAD-FMK预处理后,流式显示GCDH基因沉默神经元及赖氨酸饲养GCDH基因沉默神经元的细胞凋亡比例均明显下降。
结论线粒体膜电位变化参与赖氨酸对GCDH基因沉默纹状体神经元神经毒性作用机制,同时该神经毒性是caspase途径依赖型。
Part I The in vitro study of neurotoxicity induced by lysine in primary rat striatal neurons
Objective To culture and identify primary rat striatal neurons. To investigate the neurotoxic effect of lysine on rat striatal neurons in vitro.
Methods Striatum tissues were separated from SD rats born within24h. Trypsin digestion and serum free cultivation method were used to culture primary striatal neurons. The purity of neurons was identified by using immunohistochemical method of neuron specific enolase (NSE), using immunofluorescence and flow cytometry methods of microtubule associated protein (MAP2).24h after the intervention of different concentrations of lysine (0,5,10,15,20mmol/L) with neurons, the cell viability was determined by MTT method. Discussed the neurotoxicity induced by different concentrations of lysine in primary rat striatal neurons.
Results This method cuccessfully cultured rat striatal neurons. MAP2immunofluorescence showed that the purity of neurons was92.4±1.6%. MAP2staining flow cytometry showed that the purity of neurons was94.3±2.5%. NSE immunohistochemistry showed the purity of neurons was96.2±3.3%. The neurotoxicity induced by lysine in primary rat striatal neurons was concentration dependent. After incubated with lysine for24h, the results of MTT showed the concentration less than10mmol/L had no effect on neuron viability,15mmol/L and20mmol/L lysine reduced the viability of neurons to84.63%and45.60%respectively.
Conclusion The rat striatal neurons with high purity were successfully cultured by using trypsin digestion and serum free cultivation method. Lysine intervention for24h, the concentration of not more than10mmol/L had no neurotoxic effect on neurons. When the concentration reached more than15mmol/L, the neurotoxicity was concentration dependent. In view of that high lysine diet does not promote neurotoxicity in normal human, the concentrations of5mmol/L and10mmol/L were used in the following experiments.
Part II The neurotoxicity of targeted suppression of GCDH by lentivirus-mediated shRNA and excessive intake of lysine on rat striatal neurons
Objective To investigate the neurotoxicity induced by excessive lysine in GCDH silencing neurons by using lentivirus-mediated shRNA and excessive intake of lysine.
Methods Lentiviral vector was constructed by using a known siRNA sequence targeted suppression of GCDH gene expression. The appropriate multiplicity of infection was determined by using GFP carried by virus vector. The interference efficiency of lentivirus was determined by using Real-time PCR and Western blotting. The viability of GCDH silencing neurons incubated with lysine or not was determined by using MTT. The nuclear morphological changes in rat neurons were detected by using Hoechst33342staining. The quantity of neural apoptosis was analysed by using Annexin V-PE/7-AAD and flow cytometry.
Results shRNA was transfected into primary rat striatal neurons successfully by using lentiviral vector, and the transfection efficiency was as high as96.5%. The vector can effectively suppressed the GCDH gene expression. The expression of protein was reduced as much as80.78%. The targeted suppression of GCDH by lentivirus-mediated shRNA reduced the neuron viability to68.62%,5mmol/L and10mmol/L lysine enhanced this effect markedly, and the neurotoxicity was concentration dependent. Hoechst33342 staining showed nuclear apoptosis. Annexin V-PE/7-AAD flow quantitative analysis further verified the results of MTT analysis.
Conclusion Lentivirus-mediated shRNA vector suppressed the expression of GCDH gene effectively and stably.5mmol/L lysine had no effect on neuron viability, but induced GCDH silencing neurons apoptosis. GCDH silencing neurons incubated with addition of5mmol/L lysine can simulate the hypermetabolic condition in GA1patients. A novel model of GA1was established.
PartⅢ the mechanism of the neurotoxicity induced by lysine in GCDH silencing neurons was investigated
Objective To investigate the the mechanism of the neurotoxicity induced by lysine in GCDH silencing neurons.
Methods Mitochondrial membrane potential was monitored using TMRM staining, confocal microscope and flow cytometry. The levels of caspase3,8,9, AIF and Hsp70expression were determined by Western bloting.100μmol/L Z-VAD-FMK was added to the medium1h prior to lentiviral infection, and then the quantity of neural apoptosis was analysed by using Annexin V-PE/7-AAD and flow cytometry.
Results TMRM staining, confocal microscope and flow cytometry all showed suppression the expression of GCDH gene significantly decreased the neuron mitochondrial membrane potential, and5mmol/L lysine enhanced this decrease. The protein levels of caspases3and9were significantly upregulated by lentivirus. The combination of lysine and lentivirus intensified the upregulation of caspases3and9. Neither lentivirus nor5mmol/L lysine alone changed the level of caspase8expression, but exposure to both increased the protein level of caspase8. With Z-VAD-FMK pretreatment, the apoptotic cell fraction in cells infected with lentivirus decreased to21.87%in cells not exposed to lysine and41.66%in cells exposed to5mmol/L lysine.
Conclusion Mitochondrial membrane potential changes may be involved in the the mechanism of the neurotoxicity induced by lysine in GCDH silencing neurons. And the neurotoxicity is caspase pathway dependent.
引文
[1]Goodman SI, Markey SP, Moe PG, et al. Glutaric aciduria; a "new" disorder of amino acid metabolism. Biochem Med.1975; 12(1):12-21.
[2]Kamate M, Patil V, Chetal V, et al. Glutaric aciduria type I:A treatable neurometabolic disorder. Ann Indian Acad Neurol.2012; 15(1):31-4.
[3]Hoffmann GF, Meier-Augenstein W, Stockler S, et al. Physiology and pathophysiology of organic acids in cerebrospinal fluid. J Inherit Metab Dis.1993; 16(4):648-69.
[4]Kolker S, Christensen E, Leonard JV, et al. Diagnosis and management of glutaric aciduria type I-revised recommendations. J Inherit Metab Dis.2011; 34(3):677-94.
[5]Renaud DL. Leukoencephalopathies associated with macrocephaly. Semin Neurol. 2012;32(1):34-41.
[6]Hedlund GL, Longo N, Pasquali M. Glutaric acidemia type 1. Am J Med Genet C Semin Med Genet.2006; 142C(2):86-94.
[7]Singh P, Goraya JS, Ahluwalia A, et al. Teaching NeuroImages:Glutaric aciduria type 1 (glutaryl-CoA dehydrogenase deficiency). Neurology.2011; 77(1):e6.
[8]Harting I, Neumaier-Probst E, Seitz A, et al. Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain.2009; 132(Pt 7):1764-82.
[9]Hoffmann GF, Zschocke J. Glutaric aciduria type I:from clinical, biochemical and molecular diversity to successful therapy. J Inherit Metab Dis.1999; 22(4):381-91.
[10]Yang L, Yin H, Yang R, et al. Diagnosis, treatment and outcome of glutaric aciduria type I in Zhejiang Province, China. Med Sci Monit.2011; 17(7):PH55-9.
[11]Viau K, Ernst SL, Vanzo RJ, et al. Glutaric acidemia type 1:outcomes before and after expanded newborn screening. Mol Genet Metab.2012; 106(4):430-8.
[12]Gokmen-Ozel H, MacDonald A, Daly A, et al. Dietary practices in glutaric aciduria type 1 over 16 years. J Hum Nutr Diet.2012; 25(6):514-9.
[13]Couce ML, Lopez-Suarez O, Boveda MD, et al. Glutaric aciduria type I:Outcome of patients with early-versus late-diagnosis. Eur J Paediatr Neurol.2013. pii: S1090-3798(13)00006-8.
[14]Lee CS, Chien YH, Peng SF, et al. Promising outcomes in glutaric aciduria type I patients detected by newborn screening. Metab Brain Dis.2013; 28(1):61-7.
[15]Boy N, Haege G, Heringer J, et al. Low lysine diet in glutaric aciduria type I-effect on anthropometric and biochemical follow-up parameters. J Inherit Metab Dis.2012 Sep 13. [Epub ahead of print]
[16]K61ker S, Boy SP, Heringer J, et al. Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I-A decade of experience. Mol Genet Metab.2012; 107(1-2):72-80.
[17]Beauchamp MH, Boneh A, Anderson V. Cognitive, behavioural and adaptive profiles of children with glutaric aciduria type I detected through newborn screening. J Inherit Metab Dis.2009; 32 Suppl 1:S207-13.
[18]Mushimoto Y, Fukuda S, Hasegawa Y, et al. Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. Mol Genet Metab.2011; 102(3):343-8.
[19]Christensen E, Ribes A, Merinero B, et al. Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2004; 27(6):861-8.
[20]Keyser B, Glatzel M, Stellmer F, et al. Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. Biochim Biophys Acta.2008; 1782(6):385-90.
[21]Sauer SW, Opp S, Mahringer A, et al. Glutaric aciduria type I and methylmalonic aciduria:simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. Biochim Biophys Acta.2010; 1802(6):552-60.
[22]Jafari P, Braissant O, Bonafe L, et al. The unsolved puzzle of neuropathogenesis in glutaric aciduria type I. Mol Genet Metab.2011; 104(4):425-37.
[23]Koeller DM, Woontner M, Crnic LS, et al. Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. Hum Mol Genet.2002; 11(4):347-57.
[24]Zinnanti WJ, Lazovic J, Wolpert EB, et al. A diet-induced mouse model for glutaric aciduria type I. Brain.2006; 129(Pt 4):899-910.
[25]Sliva K, Schnierle BS. Selective gene silencing by viral delivery of short hairpin RNA. Virol J.2010; 7:248.
[26]Harper SQ, Gonzalez-Alegre P. Lentivirus-mediated RNA interference in mammalian neurons. Methods Mol Biol.2008; 442:95-112.
[27]Bhalla A, Vetanovetz CP, Morel E, et al. The location and trafficking routes of the neuronal retromer and its role in amyloid precursor protein transport. Neurobiol Dis. 2012;47(1):126-34.
[28]Ruiz M, Deglon N. Viral-mediated overexpression of mutant huntingtin to model HD in various species. Neurobiol Dis.2012; 48(2):202-11.
[29]Farazmandfar T, Khanahmad Shahreza H, Haghshenas MR, et al. Use of integrase-minus lentiviral vector for transient expression. Cell J.2012; 14(2):76-81.
[1]Funk CB, Prasad AN, Frosk P, et al. Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain.2005; 128(Pt 4):711-22.
[2]Sauer SW, Opp S, Mahringer A, et al. Glutaric aciduria type I and methylmalonic aciduria:simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. Biochim Biophys Acta.2010; 1802(6):552-60.
[3]Keyser B, Glatzel M, Stellmer F, et al. Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. Biochim Biophys Acta.2008; 1782(6):385-90.
[4]Frizzo ME, Schwarzbold C, Porciuncula LO, et al.3-hydroxyglutaric acid enhances glutamate uptake into astrocytes from cerebral cortex of young rats. Neurochem Int. 2004; 44(5):345-353.
[5]Jafari P, Braissant O, Bonafe L, et al. The unsolved puzzle of neuropathogenesis in glutaric aciduria type I. Mol Genet Metab.2011; 104(4):425-437.
[6]Twomey EL, Naughten ER, Donoghue VB, et al. Neuroimaging findings in glutaric aciduria type 1. Pediatr Radiol.2003; 33(12):823-30.
[7]Strauss KA, Donnelly P, Wintermark M. Cerebral haemodynamics in patients with glutaryl-coenzyme A dehydrogenase deficiency. Brain.2010; 133(Pt 1):76-92.
[8]Sen A, Pillay RS. Striatal necrosis in type 1 glutaric aciduria:Different stages in two siblings. J Pediatr Neurosci.2011; 6(2):146-8.
[9]Strauss KA, Lazovic J, Wintermark M, et al. Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency. Brain. 2007; 130(Pt 7):1905-20.
[10]Lamp J, Keyser B, Koeller DM, et al. Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. J Biol Chem.2011; 286(20):17777-84.
[11]Brewer GJ, Torricelli JR, Evege EK, et al. Optimized survival of hippocampal neurons in B27-supplemented Neurobasal, a new serum-free medium combination. J Neurosci Res.1993; 35(5):567-76.
[12]Peltier J, Baroncini M, Le Gars D, et al. Central neurocytomas of the lateral ventricle. A series of 35 cases with review of the literature. Neurochirurgie.2011; 57(4-6):215-9.
[13]Di Stefano G, Casoli T, Fattoretti P, et al. Distribution of map2 in hippocampus and cerebellum of young and old rats by quantitative immunohistochemistry. J Histochem Cytochem.2001; 49(8).1065-6.
[14]Miihlhausen C, Burckhardt BC, Hagos Y, et al. Membrane translocation of glutaric acid and its derivatives. J Inherit Metab Dis.2008; 31(2):188-93.
[15]Dalcin KB, Rosa RB, Schmidt AL, et al. Age and brain structural related effects of glutaric and 3-hydroxyglutaric acids on glutamate binding to plasma membranes during rat brain development. Cell Mol Neurobiol.2007; 27(6):805-18.
[1]Fu Z, Wang M, Paschke R, et al. Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate:structural bases of dehydrogenation and decarboxylation reactions. Biochemistry.2004; 43(30):9674-84.
[2]Swigonova Z, Mohsen AW, Vockley J. Acyl-CoA dehydrogenases:Dynamic history of protein family evolution. J Mol Evol.2009; 69(2):176-93.
[3]Lindner M, Gramer G, Haege G, et al. Efficacy and outcome of expanded newborn screening for metabolic diseases--report of 10 years from South-West Germany. Orphanet J Rare Dis.2011; 6:44.
[4]Christensen E, Ribes A, Merinero B, et al. Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2004; 27(6):861-8.
[5]Bross P, Frederiksen JB, Bie AS, et al. Heterozygosity for an in-frame deletion causes glutaryl-CoA dehydrogenase deficiency in a patient detected by newborn screening:investigation of the effect of the mutant allele. J Inherit Metab Dis.2012; 35(5):787-96.
[6]Strauss KA, Puffenberger EQ Robinson DL, et al. Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet C Semin Med Genet.2003; 121C(1):38-52.
[7]Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNAin Caenorhabditis elegans. Nature.1998; 391(6669):806-11.
[8]Kim VN. MicroRNA biogenesis:coordinated cropping and dicing. Nat Rev Mol Cell Biol.2005; 6(5):376-85.
[9]Harper SQ, Gonzalez-Alegre P. Lentivirus-mediated RNA interference in mammalian neurons. Methods Mol Biol.2008; 442:95-112.
[10]D'Costa J, Mansfield SG, Humeau LM. Lentiviral vectors in clinical trials:Current status. Curr Opin Mol Ther.2009; 11(5):554-64.
[11]Manilla P, Rebello T, Afable C, et al. Regulatory considerations for novel gene therapy products:a review of the process leading to the first clinical lentiviral vector. Hum Gene Ther.2005; 16(1):17-25.
[12]Schambach A, Baum C. Clinical application of lentiviral vectors-concepts and practice. Curr Gene Ther.2008; 8(6):474-82.
[13]Coutant F, Sanchez David RY, Felix T, et al. A nonintegrative lentiviral vector-based vaccine provides long-term sterile protection against malaria. PLoS One.2012; 7(11):e48644.
[14]Ruiz M, Deglon N. Viral-mediated overexpression of mutant huntingtin to model HD in various species. Neurobiol Dis.2012; 48(2):202-11.
[15]Seredenina T, Gokce O, Luthi-Carter R. Decreased striatal RGS2 expression is neuroprotective in Huntington's disease (HD) and exemplifies a compensatory aspect of HD-induced gene regulation. PLoS One.2011; 6(7):e22231.
[16]Martin E, Betuing S, Pages C, et al. Mitogen-and stress-activated protein kinase 1-induced neuroprotection in Huntington's disease:role on chromatin remodeling at the PGC-1-alpha promoter. Hum Mol Genet.2011; 20(12):2422-34.
[17]Federico A, Cardaioli E, Da Pozzo P, et al. Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci.2012; 322(1-2):254-62.
[18]Kolker S, Christensen E, Leonard JV, et al. Diagnosis and management of glutaric aciduria type I--revised recommendations. J Inherit Metab Dis.2011; 34(3):677-94.
[19]Zafeiriou DI, Zschocke J, Augoustidou-Savvopoulou P, et al. Atypical and variable clinical presentation of glutaric aciduria type I. Neuropediatrics.2000; 31(6):303-6.
[20]Bahr O, Mader I, Zschocke J, et al. Adult onset glutaric aciduria type I presenting with a leukoencephalopathy. Neurology.2002; 59(11):1802-4.
[21]Frizzo ME, Schwarzbold C, Porciuncula LO, et al.3-hydroxyglutaric acid enhances glutamate uptake into astrocytes from cerebral cortex of young rats. Neurochem Int. 2004; 44(5):345-53.
[22]Wajner M, Kolker S, Souza DO, et al. Modulation of glutamatergic and GABAergic neurotransmission in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2004; 27(6):825-8.
[23]Quincozes-Santos A, Rosa RB, Leipnitz G, et al. Induction of S100B secretion in C6 astroglial cells by the major metabolites accumulating in glutaric acidemia type I. Metab Brain Dis.2010; 25(2):191-8.
[24]Olivera-Bravo S, Fernandez A, Sarlabos MN, et al. Neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia-I. PLoS One.2011; 6(6):e20831.
[25]Funk CB, Prasad AN, Frosk P, et al. Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain.2005; 128(Pt 4):711-22.
[26]Zinnanti WJ, Lazovic J, Housman C, et al. Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. J Clin Invest. 2007; 117(11):3258-70.
[27]Lin X, Yu Y, Zhao H, et al. Overexpression of PKCalpha is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model. Carcinogenesis.2006; 27(8):1538-46.
[28]Koeller DM, Woontner M, Crnic LS, et al. Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. Hum Mol Genet.2002; 11(4):347-57.
[29]Zinnanti WJ, Lazovic J, Wolpert EB, et al. A diet-induced mouse model for glutaric aciduria type I. Brain.2006; 129(Pt 4):899-910.
[30]Kolker S, Sauer SW, Okun JG, et al. Lysine intake and neurotoxicity in glutaric aciduria type I:towards a rationale for therapy? Brain.2006; 129(Pt 8):e54.
[31]Clancy B, Finlay BL, Darlington RB, et al. Extrapolating brain development from experimental species to humans. Neurotoxicology.2007; 28(5):931-7.
[32]Bonthuis PJ, Cox KH, Searcy BT, et al. Of mice and rats:key species variations in the sexual differentiation of brain and behavior. Front Neuroendocrinol.2010; 31(3):341-58.
[33]Iannaccone PM, Jacob HJ. Rats! Dis Model Mech.2009; 2(5-6):206-10.
[34]Hirst WD, Abrahamsen B, Blaney FE, et al. Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling. Mol Pharmacol.2003; 64(6):1295-308.
[35]Dreyer JL. Lentiviral vector-mediated gene transfer and RNA silencing technology in neuronal dysfunctions. Methods Mol Biol.2010; 614:3-35.
[36]Molles BE, Maskos U, Pons S, et al. Targeted in vivo expression of nicotinic acetylcholine receptors in mouse brain using lentiviral expression vectors. J Mol Neurosci.2006; 30(1-2):105-6.
[1]McBride HM, Neuspiel M, Wasiak S. Mitochondria:more than just a powerhouse. Curr Biol.2006; 16(14):R551-60.
[2]Bueler H. Mitochondrial dynamics, cell death and the pathogenesis of Parkinson's disease. Apoptosis.2010; 15(11):1336-53.
[3]Federico A, Cardaioli E, Da Pozzo P, et al. Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci.2012; 322(1-2):254-62.
[4]Silva CG, Silva AR, Ruschel C, et al. Inhibition of energy production in vitro by glutaric acid in cerebral cortex of young rats. Metab Brain Dis.2000; 15(2):123-31.
[5]da C Ferreira G, Viegas CM, Schuck PF, et al. Glutaric acid moderately compromises energy metabolism in rat brain. Int J Dev Neurosci.2005; 23(8):687-93.
[6]Ferreira Gda C, Viegas CM, Schuck PF, et al. Glutaric acid administration impairs energy metabolism in midbrain and skeletal muscle of young rats. Neurochem Res. 2005; 30(9):1123-31.
[7]Latini A, Rodriguez M, Borba Rosa R, et al.3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats. Neuroscience.2005; 135(1):111-20.
[8]Ferreira GC, Tonin A, Schuck PF, et al. Evidence for a synergistic action of glutaric and 3-hydroxyglutaric acids disturbing rat brain energy metabolism. Int J Dev Neurosci.2007; 25(6):391-8.
[9]Ferreira Gda C, Schuck PF, Viegas CM, et al. Energy metabolism is compromised in skeletal muscle of rats chronically-treated with glutaric acid. Metab Brain Dis.2007; 22(1):111-23.
[10]Amaral AU, Seminotti B, Cecatto C, et al. Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice:a possible mechanism for brain injury in glutaric aciduria type I. Mol Genet Metab. 2012; 107(3):375-82.
[11]Taylor DM, Moser R, Regulier E, et al. MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition. J Neurosci.2013; 33(6):2313-25.
[12]Squitieri F, Maglione V, Orobello S, et al. Genotype-, aging-dependent abnormal caspase activity in Huntington disease blood cells. J Neural Transm.2011; 118(11):1599-607.
[13]Carvajal FJ, Zolezzi JM, Tapia-Rojas C, et al. Tetrahydrohyperforin Decreases Cholinergic Markers associated with Amyloid-β Plaques,4-Hydroxynonenal Formation, and Caspase-3 Activation in AβPP/PS1 mice. J Alzheimers Dis.2013 Apr 8. [Epub ahead of print]
[14]Cetin F, Yazihan N, Dincer S, et al. The Effect of Intracerebroventricular Injection of Beta Amyloid Peptide (1-42) on Caspase-3 Activity, Lipid Peroxidation, Nitric Oxide and NOS Expression in Young Adult and Aged Rat Brain. Turk Neurosurg. 2013;23(2):144-50.
[15]Tian F, Fu X, Gao J, et al. Caspase-3 mediates apoptosis of striatal cells in GA I rat model. J Huazhong Univ Sci Technolog Med Sci.2012; 32(1):107-12.
[16]Cao Z, LePage KT, Frederick MO, et al. Involvement of caspase activation in azaspiracid-induced neurotoxicity in neocortical neurons. Toxicol Sci.2010; 114(2):323-34.
[17]Nagley P, Higgins GC, Atkin JD, et al. Multifaceted deaths orchestrated by mitochondria in neurones. Biochim Biophys Acta.2010; 1802(1):167-85.
[18]Moran M, Moreno-Lastres D, Marin-Buera L, et al. Mitochondrial respiratory chain dysfunction:implications in neurodegeneration. Free Radic Biol Med.2012; 53(3):595-609.
[19]Schon EA, Przedborski S. Mitochondria:the next (neurode)generation. Neuron. 2011 Jun23;70(6):1033-53.
[20]Perez-Pinzon MA, Stetler RA, Fiskum G. Novel mitochondrial targets for neuroprotection. J Cereb Blood Flow Metab.2012; 32(7):1362-76.
[21]Wajner M, Goodman SI. Disruption of mitochondrial homeostasis in organic acidurias:insights from human and animal studies. J Bioenerg Biomembr.2011; 43(1):31-8.
[22]Amaral AU, Seminotti B, Cecatto C, et al. Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice:a possible mechanism for brain injury in glutaric aciduria type I. Mol Genet Metab. 2012; 107(3):375-82.
[23]Amaral AU, Cecatto C, Seminotti B, et al. Marked reduction of Na(+), K(+)-ATPase and creatine kinase activities induced by acute lysine administration in glutaryl-CoA dehydrogenase deficient mice. Mol Genet Metab.2012; 107(1-2):81-6.
[24]Kroemer G, Zamzami N, Susin SA. Mitochondrial control of apoptosis. Immunol Today.1997; 18(1):44-51.
[25]Green DR, Reed JC. Mitochondria and apoptosis. Science.1998; 281(5381):1309-12.
[26]Joshi DC, Bakowska JC. Determination of mitochondrial membrane potential and reactive oxygen species in live rat cortical neurons. J Vis Exp.2011; (51).
[27]Guerrero AD, Schmitz I, Chen M, et al. Promotion of Caspase Activation by Caspase-9-mediated Feedback Amplification of Mitochondrial Damage. J Clin Cell Immunol.2012; 3(3).
[28]Bodai L, Marsh JL. A novel target for Huntington's disease:ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington's disease and its upregulation ameliorates pathology. Bioessays.2012; 34(2):142-8.
[29]Rohn TT. The role of caspases in Alzheimer's disease; potential novel therapeutic opportunities. Apoptosis.2010; 15(11):1403-9.
[1]Goodman SI, Markey SP, Moe PG, et al. Glutaric aciduria; a "new" disorder of amino acid metabolism. Biochem Med.1975,12(1):12-21.
[2]Kolker S, Christensen E, Leonard JV, et al. Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I). J Inherit Metab Dis.2007,30(1):5-22.
[3]Yang L, Yin H, Yang R, et al. Diagnosis, treatment and outcome of glutaric aciduria type I in Zhejiang Province, China. Med Sci Monit.2011,17(7):PH55-59
[4]Kolker S, Christensen E, Leonard JV, et al. Diagnosis and management of glutaric aciduria type I-revised recommendations. J Inherit Metab Dis.2011, 34(3):677-694.
[5]Greenberg CR, Duncan AM, Gregory CA, et al. Assignment of human glutaryl-CoA dehydrogenase gene (GCDH) to the short arm of chromosome 19 (19p13.2) by in situ hybridization and somatic cell hybrid analysis. Genomics.1994,21(1):289-290.
[6]Mushimoto Y, Fukuda S, Hasegawa Y, et al. Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. Mol Genet Metab.2011, 102(3):343-348.
[7]Tang NL, Hui J, Law LK, et al. Recurrent and novel mutations of GCDH gene in Chinese glutaric acidemia type I families. Hum Mutat.2000,16(5):446.
[8]Keyser B, Muhlhausen C, Dickmanns A, et al. Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH). Hum Mol Genet.2008,17(24):3854-3863.
[9]Christensen E, Ribes A, Merinero B, et al. Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2004,27(6):861-868.
[10]Hedlund GL, Longo N, Pasquali M. Glutaric acidemia type 1. Am J Med Genet C Semin Med Genet.2006,142C(2):86-94.
[11]Funk CB, Prasad AN, Frosk P, et al. Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain.2005,128(Pt 4):711-722.
[12]Sauer SW, Opp S, Mahringer A, et al. Glutaric aciduria type I and methylmalonic aciduria:Simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. Biochim Biophys Acta.2010,1802(6):552-560.
[13]Koeller DM, Sauer S, Wajner M, et al. Animal models for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2004,27(6):813-818.
[14]Sauer SW, Okun JG, Fricker G, et al. Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem.2006,97(3):899-910.
[15]Keyser B, Glatzel M, Stellmer F, et al. Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. Biochim Biophys Acta.2008,1782(6):385-390.
[16]Sauer SW. Biochemistry and bioenergetics of glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2007,30(5):673-680.
[17]Kolker S, Hoffmann GF, Schor DS, et al. Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcar-nitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics.2003,34(5):253-260.
[18]Bjugstad KB, Zawada WM, Goodman S, et al. IGF-1 and bFGF reduce glutaric acid and 3-hydroxyglutaric toxicity in striatal cultures. J Inherit Metab Dis.2001, 24(6):631-647.
[19]Freudenberg F, Lukacs Z, Ullrich K.3-Hydroxyglutaric acid fails to affect the viability of primary neuronal rat cells. Neurobiol Dis.2004,16(3):581-584.
[20]Varadkar S, Surtees R. Glutaric aciduria type I and kynurenine pathway metabolites: Amodioed hypothesis. J Inherit Metab Dis.2004,27(6):835-842.
[21]Wajner M, Kolker S, Souza DO, et al. Modulation of glutamatergic and GABAergic neurotransmission in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2004,27(6):825-828.
[22]Rosa RB, Dalcin KB, Schmidt AL, et al. Evidence that glutaric acid reduces glutamate uptake by cerebral cortex of infant rats. Life Sci.2007, 81(25-26):1668-1676.
[23]Porciuncula LO, Emanuelli T, Tavares RG, et al. Glutaric acid stimulates glutamate binding and astrocytic uptake and inhibits vesicular glutamate uptake in forebrain from young rats. Neurochem Int.2004,45(7):1075-86.
[24]Sauer SW, Okun JG, Schwab MA, et al. Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency:a role for glutaryl-coenzyme A. J Biol Chem.2005, 280(23):21830-21836.
[25]Ferreira Gda C, Schuck PF, Viegas CM, et al. Energy metabolism is compromised in skeletal muscle of rats chronically-treated with glutaric acid. Metab Brain Dis.2007, 22(1):111-123.
[26]da C Ferreira G, Viegas CM, Schuck PF, et al. Glutaric acid moderately compromises energy metabolism in rat brain. Int J Dev Neurosci.2005,23(8):687-693.
[27]Latini A, Rodriguez M, Borba Rosa R, et al.3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats. Neuroscience.2005, 135(1):111一120.
[28]Ferreira GC, Tonin A, Schuck PF, et al. Evidence for a synergistic action of glutaric and 3-hydroxyglutaric acids disturbing rat brain energy metabolism. Int J Dev Neurosci.2007,25(6):391-398.
[29]Schuck PF, Tonin A, da Costa Ferreira G, et al. In vitro effect of quinolinic acid on energy metabolism in brain of young rats. Neurosci Res.2007,57(2):277-288.
[30]Lamp J, Keyser B, Koeller DM, et al. Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. J Biol Chem.2011, 286(20):17777-17784.
[31]Magni DV, Bruning CA, Gai BM, et al. m-Trifluoromethyl diphenyl diselenide attenuates glutaric acid-induced seizures and oxidative stress in rat pups: involvement of the y-aminobutyric acidergic system. J Neurosci Res.2012, 90(9):1723-31.
[32]Fernandez-Checa JC, Fernandez A, Morales A, et al. Oxidative stress and altered mitochondrial function in neurodegenerative diseases:lessons from mouse models. CNS Neurol Disord Drug Targets.2010,9(4):439-454.
[33]Latini A, Borba Rosa R, Scussiato K, et al.3-Hydroxyglutaric acid induces oxidative stress and decreases the antioxidant defenses in cerebral cortex of young rats. Brain Res.2002,956(2):367-373.
[34]de Oliveira Marques F, Hagen ME, Pederzolli CD, et al. Glutaric acid induces oxidative stress in brain of young rats. Brain Res.2003,964(1):153-158.
[35]Leipnitz G, Schumacher C, Scussiato K, et al. Quinolinic acid reduces the antioxidant defenses in cerebral cortex of young rats. Int J Dev Neurosci.2005, 23(8):695-701.
[36]Seminotti B, Amaral AU, da Rosa MS, et al. Disruption of brain redox homeostasis in glutaryl-CoA dehydrogenase deficient mice treated with high dietary lysine supplementation. Mol Genet Metab.2013,108(1):30-9.
[37]Latini A, Ferreira GC, Scussiato K, et al. Induction of oxidative stress by chronic and acute glutaric acid administration to rats. Cell Mol Neurobiol.2007, 27(4):423-438.
[38]Olivera S, Fernandez A, Latini A, et al. Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesis. Neurobiol Dis.2008,32(3):528-534.
[39]Quincozes-Santos A, Rosa RB, Leipnitz G, et al. Induction of S100B secretion in C6 astroglial cells by the major metabolites accumulating in glutaric acidemia type 1. Metab Brain Dis.2010,25(2):191-198.
[40]Jafari P, Braissant O, Zavadakova P, et al. Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I. PLoS One.2013, 8(1):e53735.
[41]Olivera-Bravo S, Fernandez A, Sarlabos MN, et al. Neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia I. PLoS One.2011,6(6):e20831.
[42]Magni DV, Souza MA, Oliveira AP, et al. Lipopolysaccharide enhances glutaric acid-induced seizure susceptibility in rat pups:behavioral and electroencephalographic approach. Epilepsy Res.2011,93(2-3):138-148.
[43]Muhlhausen C, Ott N, Chalajour F, et al. Endothelial effects of 3-hydroxyglutaric acid:implications for glutaric aciduria type I. Pediatr Res.2006,59(2):196-202.
[44]Marti-Masso JF, Ruiz-Martinez J, Makarov V, et al. Exome sequencing identifies GCDH (glutaryl-CoA dehydrogenase) mutations as a cause of a progressive form of early-onset generalized dystonia. Hum Genet.2012,131(3):435-42.
[45]Carman KB, Aydogdu SD, Yakut A, et al. Glutaric aciduria type 1 presenting as subdural haematoma. J Paediatr Child Health.2012,48(8):712.
[46]Bishop FS, Liu JK, McCall TD, et al. Glutaric aciduria type 1 presenting as bilateral subdural hematomas mimicking nonaccidental trauma. J Neurosurg.2007, 106(3 Suppl Pediatrics):222-226.
[47]Heringer J, Boy SP, Ensenauer R, et al. Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol.2010,68(5):743-752.
[48]Kolker S, Garbade SF, Greenberg CR, et al. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res.2006,59(6):840-847.
[49]Lopez-Laso E, Garcia-Villoria J, Martin E, et al. Classic and late-onset neurological disease in two siblings with glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2007,30(6):979.
[50]McClelland VM, Bakalinova DB, Hendriksz C, et al. Glutaric aciduria type 1 presenting with epilepsy. Dev Med Child Neurol.2009,51(3):235-239.
[51]Renaud DL. Leukoencephalopathies associated with macrocephaly. Semin Neurol. 2012,32(1):34-41.
[52]Jamuar SS, Newton SA, Prabhu SP, et al. Rhabdomyolysis, acute renal failure, and cardiac arrest secondary to status dystonicus in a child with glutaric aciduria type I. Mol Genet Metab.2012,106(4):488-90.
[53]齐朝月,宋金青,肖江喜,等.戊二酸尿症I型患者的临床与脑磁共振成像特点.中国医刊.2006,41：26-29.
[54]Al-Dirbashi OY, Kolker S, Ng D, et al. Diagnosis of glutaric aciduria type 1 by measuring 3-hydroxyglutaric acid in dried urine spots by liquid chromatography tandem mass spectrometry. J Inherit Metab Dis.2011,34(1):173-180.
[55]韩连书,叶军,邱文娟,等.串联质谱联合气相色谱-质谱检测遗传代谢病.中华医学杂志.2008,88(30)：2122-2126.
[56]Mushimoto Y, Hasegawa Y, Kobayashi H, et al. Enzymatic evaluation of glutaric acidemia type 1 by an in vitro probe assay of acylcarnitine profiling using fibroblasts and electrospray ionization/tandem mass spectrometry (MS/MS). J Chromatogr B Analyt Technol Biomed Life Sci.2009,877(25):2648-2651.
[57]Greenberg CR, Prasad AN, Dilling LA, et al. Outcome of the three years of a DNA-based neonatal screening program for glutaric aciduria type I in Manitoba and Northwestern Ontaria, Canada. Mol Genet Metab.2002,75(1):70-78.
[58]Moore T, Le A, Cowan TM. An improved LC-MS/MS method for the detection of classic and low excretor glutaric acidemia type 1. J Inherit Metab Dis.2012, 35(3):431-5.
[59]娄燕,尹娜,陈凤琴,等.串联质谱技术选择性筛查遗传代谢病高危患儿552例初步分析.中国当代儿科杂志.2011,13(4)：296-299.
[60]Righini A, Fiori L, Parazzini C, et al. Early prenatal magnetic resonance imaging of glutaric aciduria type 1:case report. J Comput Assist Tomogr.2010,34(3):446-448.
[61]Ituk US, Allen TK, Habib AS. The peripartum management of a patient with glutaric aciduria type 1. J Clin Anesth.2013,25(2):141-5.
[62]Strauss KA, Brumbaugh J, Duffy A, et al. Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency:focus on cerebral amino acid influx. Mol Genet Metab.2011, 104(1-2):93-106.
[63]Tsiotou AG, Malisiova A, Bouzelos N, et al. The child with glutaric aciduria type I: anesthetic and perioperative management. J Anesth.2011,25(2):301-4.
[64]姚生,刘建国,于健,等.戊二酸尿症Ⅰ型患者的临床、影像与病理特点.中国神经免疫学和神经病学杂志.2008,15：15-18.
[2]Kamate M, Patil V, Chetal V, et al. Glutaric aciduria type I:A treatable neurometabolic disorder. Ann Indian Acad Neurol.2012; 15(1):31-4.
[3]Hoffmann GF, Meier-Augenstein W, Stockler S, et al. Physiology and pathophysiology of organic acids in cerebrospinal fluid. J Inherit Metab Dis.1993; 16(4):648-69.
[4]Kolker S, Christensen E, Leonard JV, et al. Diagnosis and management of glutaric aciduria type I-revised recommendations. J Inherit Metab Dis.2011; 34(3):677-94.
[5]Renaud DL. Leukoencephalopathies associated with macrocephaly. Semin Neurol. 2012;32(1):34-41.
[6]Hedlund GL, Longo N, Pasquali M. Glutaric acidemia type 1. Am J Med Genet C Semin Med Genet.2006; 142C(2):86-94.
[7]Singh P, Goraya JS, Ahluwalia A, et al. Teaching NeuroImages:Glutaric aciduria type 1 (glutaryl-CoA dehydrogenase deficiency). Neurology.2011; 77(1):e6.
[8]Harting I, Neumaier-Probst E, Seitz A, et al. Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain.2009; 132(Pt 7):1764-82.
[9]Hoffmann GF, Zschocke J. Glutaric aciduria type I:from clinical, biochemical and molecular diversity to successful therapy. J Inherit Metab Dis.1999; 22(4):381-91.
[10]Yang L, Yin H, Yang R, et al. Diagnosis, treatment and outcome of glutaric aciduria type I in Zhejiang Province, China. Med Sci Monit.2011; 17(7):PH55-9.
[11]Viau K, Ernst SL, Vanzo RJ, et al. Glutaric acidemia type 1:outcomes before and after expanded newborn screening. Mol Genet Metab.2012; 106(4):430-8.
[12]Gokmen-Ozel H, MacDonald A, Daly A, et al. Dietary practices in glutaric aciduria type 1 over 16 years. J Hum Nutr Diet.2012; 25(6):514-9.
[13]Couce ML, Lopez-Suarez O, Boveda MD, et al. Glutaric aciduria type I:Outcome of patients with early-versus late-diagnosis. Eur J Paediatr Neurol.2013. pii: S1090-3798(13)00006-8.
[14]Lee CS, Chien YH, Peng SF, et al. Promising outcomes in glutaric aciduria type I patients detected by newborn screening. Metab Brain Dis.2013; 28(1):61-7.
[15]Boy N, Haege G, Heringer J, et al. Low lysine diet in glutaric aciduria type I-effect on anthropometric and biochemical follow-up parameters. J Inherit Metab Dis.2012 Sep 13. [Epub ahead of print]
[16]K61ker S, Boy SP, Heringer J, et al. Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I-A decade of experience. Mol Genet Metab.2012; 107(1-2):72-80.
[17]Beauchamp MH, Boneh A, Anderson V. Cognitive, behavioural and adaptive profiles of children with glutaric aciduria type I detected through newborn screening. J Inherit Metab Dis.2009; 32 Suppl 1:S207-13.
[18]Mushimoto Y, Fukuda S, Hasegawa Y, et al. Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. Mol Genet Metab.2011; 102(3):343-8.
[19]Christensen E, Ribes A, Merinero B, et al. Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2004; 27(6):861-8.
[20]Keyser B, Glatzel M, Stellmer F, et al. Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. Biochim Biophys Acta.2008; 1782(6):385-90.
[21]Sauer SW, Opp S, Mahringer A, et al. Glutaric aciduria type I and methylmalonic aciduria:simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. Biochim Biophys Acta.2010; 1802(6):552-60.
[22]Jafari P, Braissant O, Bonafe L, et al. The unsolved puzzle of neuropathogenesis in glutaric aciduria type I. Mol Genet Metab.2011; 104(4):425-37.
[23]Koeller DM, Woontner M, Crnic LS, et al. Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. Hum Mol Genet.2002; 11(4):347-57.
[24]Zinnanti WJ, Lazovic J, Wolpert EB, et al. A diet-induced mouse model for glutaric aciduria type I. Brain.2006; 129(Pt 4):899-910.
[25]Sliva K, Schnierle BS. Selective gene silencing by viral delivery of short hairpin RNA. Virol J.2010; 7:248.
[26]Harper SQ, Gonzalez-Alegre P. Lentivirus-mediated RNA interference in mammalian neurons. Methods Mol Biol.2008; 442:95-112.
[27]Bhalla A, Vetanovetz CP, Morel E, et al. The location and trafficking routes of the neuronal retromer and its role in amyloid precursor protein transport. Neurobiol Dis. 2012;47(1):126-34.
[28]Ruiz M, Deglon N. Viral-mediated overexpression of mutant huntingtin to model HD in various species. Neurobiol Dis.2012; 48(2):202-11.
[29]Farazmandfar T, Khanahmad Shahreza H, Haghshenas MR, et al. Use of integrase-minus lentiviral vector for transient expression. Cell J.2012; 14(2):76-81.
[1]Funk CB, Prasad AN, Frosk P, et al. Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain.2005; 128(Pt 4):711-22.
[2]Sauer SW, Opp S, Mahringer A, et al. Glutaric aciduria type I and methylmalonic aciduria:simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. Biochim Biophys Acta.2010; 1802(6):552-60.
[3]Keyser B, Glatzel M, Stellmer F, et al. Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. Biochim Biophys Acta.2008; 1782(6):385-90.
[4]Frizzo ME, Schwarzbold C, Porciuncula LO, et al.3-hydroxyglutaric acid enhances glutamate uptake into astrocytes from cerebral cortex of young rats. Neurochem Int. 2004; 44(5):345-353.
[5]Jafari P, Braissant O, Bonafe L, et al. The unsolved puzzle of neuropathogenesis in glutaric aciduria type I. Mol Genet Metab.2011; 104(4):425-437.
[6]Twomey EL, Naughten ER, Donoghue VB, et al. Neuroimaging findings in glutaric aciduria type 1. Pediatr Radiol.2003; 33(12):823-30.
[7]Strauss KA, Donnelly P, Wintermark M. Cerebral haemodynamics in patients with glutaryl-coenzyme A dehydrogenase deficiency. Brain.2010; 133(Pt 1):76-92.
[8]Sen A, Pillay RS. Striatal necrosis in type 1 glutaric aciduria:Different stages in two siblings. J Pediatr Neurosci.2011; 6(2):146-8.
[9]Strauss KA, Lazovic J, Wintermark M, et al. Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency. Brain. 2007; 130(Pt 7):1905-20.
[10]Lamp J, Keyser B, Koeller DM, et al. Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. J Biol Chem.2011; 286(20):17777-84.
[11]Brewer GJ, Torricelli JR, Evege EK, et al. Optimized survival of hippocampal neurons in B27-supplemented Neurobasal, a new serum-free medium combination. J Neurosci Res.1993; 35(5):567-76.
[12]Peltier J, Baroncini M, Le Gars D, et al. Central neurocytomas of the lateral ventricle. A series of 35 cases with review of the literature. Neurochirurgie.2011; 57(4-6):215-9.
[13]Di Stefano G, Casoli T, Fattoretti P, et al. Distribution of map2 in hippocampus and cerebellum of young and old rats by quantitative immunohistochemistry. J Histochem Cytochem.2001; 49(8).1065-6.
[14]Miihlhausen C, Burckhardt BC, Hagos Y, et al. Membrane translocation of glutaric acid and its derivatives. J Inherit Metab Dis.2008; 31(2):188-93.
[15]Dalcin KB, Rosa RB, Schmidt AL, et al. Age and brain structural related effects of glutaric and 3-hydroxyglutaric acids on glutamate binding to plasma membranes during rat brain development. Cell Mol Neurobiol.2007; 27(6):805-18.
[1]Fu Z, Wang M, Paschke R, et al. Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate:structural bases of dehydrogenation and decarboxylation reactions. Biochemistry.2004; 43(30):9674-84.
[2]Swigonova Z, Mohsen AW, Vockley J. Acyl-CoA dehydrogenases:Dynamic history of protein family evolution. J Mol Evol.2009; 69(2):176-93.
[3]Lindner M, Gramer G, Haege G, et al. Efficacy and outcome of expanded newborn screening for metabolic diseases--report of 10 years from South-West Germany. Orphanet J Rare Dis.2011; 6:44.
[4]Christensen E, Ribes A, Merinero B, et al. Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2004; 27(6):861-8.
[5]Bross P, Frederiksen JB, Bie AS, et al. Heterozygosity for an in-frame deletion causes glutaryl-CoA dehydrogenase deficiency in a patient detected by newborn screening:investigation of the effect of the mutant allele. J Inherit Metab Dis.2012; 35(5):787-96.
[6]Strauss KA, Puffenberger EQ Robinson DL, et al. Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet C Semin Med Genet.2003; 121C(1):38-52.
[7]Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNAin Caenorhabditis elegans. Nature.1998; 391(6669):806-11.
[8]Kim VN. MicroRNA biogenesis:coordinated cropping and dicing. Nat Rev Mol Cell Biol.2005; 6(5):376-85.
[9]Harper SQ, Gonzalez-Alegre P. Lentivirus-mediated RNA interference in mammalian neurons. Methods Mol Biol.2008; 442:95-112.
[10]D'Costa J, Mansfield SG, Humeau LM. Lentiviral vectors in clinical trials:Current status. Curr Opin Mol Ther.2009; 11(5):554-64.
[11]Manilla P, Rebello T, Afable C, et al. Regulatory considerations for novel gene therapy products:a review of the process leading to the first clinical lentiviral vector. Hum Gene Ther.2005; 16(1):17-25.
[12]Schambach A, Baum C. Clinical application of lentiviral vectors-concepts and practice. Curr Gene Ther.2008; 8(6):474-82.
[13]Coutant F, Sanchez David RY, Felix T, et al. A nonintegrative lentiviral vector-based vaccine provides long-term sterile protection against malaria. PLoS One.2012; 7(11):e48644.
[14]Ruiz M, Deglon N. Viral-mediated overexpression of mutant huntingtin to model HD in various species. Neurobiol Dis.2012; 48(2):202-11.
[15]Seredenina T, Gokce O, Luthi-Carter R. Decreased striatal RGS2 expression is neuroprotective in Huntington's disease (HD) and exemplifies a compensatory aspect of HD-induced gene regulation. PLoS One.2011; 6(7):e22231.
[16]Martin E, Betuing S, Pages C, et al. Mitogen-and stress-activated protein kinase 1-induced neuroprotection in Huntington's disease:role on chromatin remodeling at the PGC-1-alpha promoter. Hum Mol Genet.2011; 20(12):2422-34.
[17]Federico A, Cardaioli E, Da Pozzo P, et al. Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci.2012; 322(1-2):254-62.
[18]Kolker S, Christensen E, Leonard JV, et al. Diagnosis and management of glutaric aciduria type I--revised recommendations. J Inherit Metab Dis.2011; 34(3):677-94.
[19]Zafeiriou DI, Zschocke J, Augoustidou-Savvopoulou P, et al. Atypical and variable clinical presentation of glutaric aciduria type I. Neuropediatrics.2000; 31(6):303-6.
[20]Bahr O, Mader I, Zschocke J, et al. Adult onset glutaric aciduria type I presenting with a leukoencephalopathy. Neurology.2002; 59(11):1802-4.
[21]Frizzo ME, Schwarzbold C, Porciuncula LO, et al.3-hydroxyglutaric acid enhances glutamate uptake into astrocytes from cerebral cortex of young rats. Neurochem Int. 2004; 44(5):345-53.
[22]Wajner M, Kolker S, Souza DO, et al. Modulation of glutamatergic and GABAergic neurotransmission in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2004; 27(6):825-8.
[23]Quincozes-Santos A, Rosa RB, Leipnitz G, et al. Induction of S100B secretion in C6 astroglial cells by the major metabolites accumulating in glutaric acidemia type I. Metab Brain Dis.2010; 25(2):191-8.
[24]Olivera-Bravo S, Fernandez A, Sarlabos MN, et al. Neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia-I. PLoS One.2011; 6(6):e20831.
[25]Funk CB, Prasad AN, Frosk P, et al. Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain.2005; 128(Pt 4):711-22.
[26]Zinnanti WJ, Lazovic J, Housman C, et al. Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. J Clin Invest. 2007; 117(11):3258-70.
[27]Lin X, Yu Y, Zhao H, et al. Overexpression of PKCalpha is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model. Carcinogenesis.2006; 27(8):1538-46.
[28]Koeller DM, Woontner M, Crnic LS, et al. Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. Hum Mol Genet.2002; 11(4):347-57.
[29]Zinnanti WJ, Lazovic J, Wolpert EB, et al. A diet-induced mouse model for glutaric aciduria type I. Brain.2006; 129(Pt 4):899-910.
[30]Kolker S, Sauer SW, Okun JG, et al. Lysine intake and neurotoxicity in glutaric aciduria type I:towards a rationale for therapy? Brain.2006; 129(Pt 8):e54.
[31]Clancy B, Finlay BL, Darlington RB, et al. Extrapolating brain development from experimental species to humans. Neurotoxicology.2007; 28(5):931-7.
[32]Bonthuis PJ, Cox KH, Searcy BT, et al. Of mice and rats:key species variations in the sexual differentiation of brain and behavior. Front Neuroendocrinol.2010; 31(3):341-58.
[33]Iannaccone PM, Jacob HJ. Rats! Dis Model Mech.2009; 2(5-6):206-10.
[34]Hirst WD, Abrahamsen B, Blaney FE, et al. Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling. Mol Pharmacol.2003; 64(6):1295-308.
[35]Dreyer JL. Lentiviral vector-mediated gene transfer and RNA silencing technology in neuronal dysfunctions. Methods Mol Biol.2010; 614:3-35.
[36]Molles BE, Maskos U, Pons S, et al. Targeted in vivo expression of nicotinic acetylcholine receptors in mouse brain using lentiviral expression vectors. J Mol Neurosci.2006; 30(1-2):105-6.
[1]McBride HM, Neuspiel M, Wasiak S. Mitochondria:more than just a powerhouse. Curr Biol.2006; 16(14):R551-60.
[2]Bueler H. Mitochondrial dynamics, cell death and the pathogenesis of Parkinson's disease. Apoptosis.2010; 15(11):1336-53.
[3]Federico A, Cardaioli E, Da Pozzo P, et al. Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci.2012; 322(1-2):254-62.
[4]Silva CG, Silva AR, Ruschel C, et al. Inhibition of energy production in vitro by glutaric acid in cerebral cortex of young rats. Metab Brain Dis.2000; 15(2):123-31.
[5]da C Ferreira G, Viegas CM, Schuck PF, et al. Glutaric acid moderately compromises energy metabolism in rat brain. Int J Dev Neurosci.2005; 23(8):687-93.
[6]Ferreira Gda C, Viegas CM, Schuck PF, et al. Glutaric acid administration impairs energy metabolism in midbrain and skeletal muscle of young rats. Neurochem Res. 2005; 30(9):1123-31.
[7]Latini A, Rodriguez M, Borba Rosa R, et al.3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats. Neuroscience.2005; 135(1):111-20.
[8]Ferreira GC, Tonin A, Schuck PF, et al. Evidence for a synergistic action of glutaric and 3-hydroxyglutaric acids disturbing rat brain energy metabolism. Int J Dev Neurosci.2007; 25(6):391-8.
[9]Ferreira Gda C, Schuck PF, Viegas CM, et al. Energy metabolism is compromised in skeletal muscle of rats chronically-treated with glutaric acid. Metab Brain Dis.2007; 22(1):111-23.
[10]Amaral AU, Seminotti B, Cecatto C, et al. Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice:a possible mechanism for brain injury in glutaric aciduria type I. Mol Genet Metab. 2012; 107(3):375-82.
[11]Taylor DM, Moser R, Regulier E, et al. MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition. J Neurosci.2013; 33(6):2313-25.
[12]Squitieri F, Maglione V, Orobello S, et al. Genotype-, aging-dependent abnormal caspase activity in Huntington disease blood cells. J Neural Transm.2011; 118(11):1599-607.
[13]Carvajal FJ, Zolezzi JM, Tapia-Rojas C, et al. Tetrahydrohyperforin Decreases Cholinergic Markers associated with Amyloid-β Plaques,4-Hydroxynonenal Formation, and Caspase-3 Activation in AβPP/PS1 mice. J Alzheimers Dis.2013 Apr 8. [Epub ahead of print]
[14]Cetin F, Yazihan N, Dincer S, et al. The Effect of Intracerebroventricular Injection of Beta Amyloid Peptide (1-42) on Caspase-3 Activity, Lipid Peroxidation, Nitric Oxide and NOS Expression in Young Adult and Aged Rat Brain. Turk Neurosurg. 2013;23(2):144-50.
[15]Tian F, Fu X, Gao J, et al. Caspase-3 mediates apoptosis of striatal cells in GA I rat model. J Huazhong Univ Sci Technolog Med Sci.2012; 32(1):107-12.
[16]Cao Z, LePage KT, Frederick MO, et al. Involvement of caspase activation in azaspiracid-induced neurotoxicity in neocortical neurons. Toxicol Sci.2010; 114(2):323-34.
[17]Nagley P, Higgins GC, Atkin JD, et al. Multifaceted deaths orchestrated by mitochondria in neurones. Biochim Biophys Acta.2010; 1802(1):167-85.
[18]Moran M, Moreno-Lastres D, Marin-Buera L, et al. Mitochondrial respiratory chain dysfunction:implications in neurodegeneration. Free Radic Biol Med.2012; 53(3):595-609.
[19]Schon EA, Przedborski S. Mitochondria:the next (neurode)generation. Neuron. 2011 Jun23;70(6):1033-53.
[20]Perez-Pinzon MA, Stetler RA, Fiskum G. Novel mitochondrial targets for neuroprotection. J Cereb Blood Flow Metab.2012; 32(7):1362-76.
[21]Wajner M, Goodman SI. Disruption of mitochondrial homeostasis in organic acidurias:insights from human and animal studies. J Bioenerg Biomembr.2011; 43(1):31-8.
[22]Amaral AU, Seminotti B, Cecatto C, et al. Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice:a possible mechanism for brain injury in glutaric aciduria type I. Mol Genet Metab. 2012; 107(3):375-82.
[23]Amaral AU, Cecatto C, Seminotti B, et al. Marked reduction of Na(+), K(+)-ATPase and creatine kinase activities induced by acute lysine administration in glutaryl-CoA dehydrogenase deficient mice. Mol Genet Metab.2012; 107(1-2):81-6.
[24]Kroemer G, Zamzami N, Susin SA. Mitochondrial control of apoptosis. Immunol Today.1997; 18(1):44-51.
[25]Green DR, Reed JC. Mitochondria and apoptosis. Science.1998; 281(5381):1309-12.
[26]Joshi DC, Bakowska JC. Determination of mitochondrial membrane potential and reactive oxygen species in live rat cortical neurons. J Vis Exp.2011; (51).
[27]Guerrero AD, Schmitz I, Chen M, et al. Promotion of Caspase Activation by Caspase-9-mediated Feedback Amplification of Mitochondrial Damage. J Clin Cell Immunol.2012; 3(3).
[28]Bodai L, Marsh JL. A novel target for Huntington's disease:ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington's disease and its upregulation ameliorates pathology. Bioessays.2012; 34(2):142-8.
[29]Rohn TT. The role of caspases in Alzheimer's disease; potential novel therapeutic opportunities. Apoptosis.2010; 15(11):1403-9.
[1]Goodman SI, Markey SP, Moe PG, et al. Glutaric aciduria; a "new" disorder of amino acid metabolism. Biochem Med.1975,12(1):12-21.
[2]Kolker S, Christensen E, Leonard JV, et al. Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I). J Inherit Metab Dis.2007,30(1):5-22.
[3]Yang L, Yin H, Yang R, et al. Diagnosis, treatment and outcome of glutaric aciduria type I in Zhejiang Province, China. Med Sci Monit.2011,17(7):PH55-59
[4]Kolker S, Christensen E, Leonard JV, et al. Diagnosis and management of glutaric aciduria type I-revised recommendations. J Inherit Metab Dis.2011, 34(3):677-694.
[5]Greenberg CR, Duncan AM, Gregory CA, et al. Assignment of human glutaryl-CoA dehydrogenase gene (GCDH) to the short arm of chromosome 19 (19p13.2) by in situ hybridization and somatic cell hybrid analysis. Genomics.1994,21(1):289-290.
[6]Mushimoto Y, Fukuda S, Hasegawa Y, et al. Clinical and molecular investigation of 19 Japanese cases of glutaric acidemia type 1. Mol Genet Metab.2011, 102(3):343-348.
[7]Tang NL, Hui J, Law LK, et al. Recurrent and novel mutations of GCDH gene in Chinese glutaric acidemia type I families. Hum Mutat.2000,16(5):446.
[8]Keyser B, Muhlhausen C, Dickmanns A, et al. Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH). Hum Mol Genet.2008,17(24):3854-3863.
[9]Christensen E, Ribes A, Merinero B, et al. Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2004,27(6):861-868.
[10]Hedlund GL, Longo N, Pasquali M. Glutaric acidemia type 1. Am J Med Genet C Semin Med Genet.2006,142C(2):86-94.
[11]Funk CB, Prasad AN, Frosk P, et al. Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain.2005,128(Pt 4):711-722.
[12]Sauer SW, Opp S, Mahringer A, et al. Glutaric aciduria type I and methylmalonic aciduria:Simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. Biochim Biophys Acta.2010,1802(6):552-560.
[13]Koeller DM, Sauer S, Wajner M, et al. Animal models for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2004,27(6):813-818.
[14]Sauer SW, Okun JG, Fricker G, et al. Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem.2006,97(3):899-910.
[15]Keyser B, Glatzel M, Stellmer F, et al. Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. Biochim Biophys Acta.2008,1782(6):385-390.
[16]Sauer SW. Biochemistry and bioenergetics of glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2007,30(5):673-680.
[17]Kolker S, Hoffmann GF, Schor DS, et al. Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcar-nitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics.2003,34(5):253-260.
[18]Bjugstad KB, Zawada WM, Goodman S, et al. IGF-1 and bFGF reduce glutaric acid and 3-hydroxyglutaric toxicity in striatal cultures. J Inherit Metab Dis.2001, 24(6):631-647.
[19]Freudenberg F, Lukacs Z, Ullrich K.3-Hydroxyglutaric acid fails to affect the viability of primary neuronal rat cells. Neurobiol Dis.2004,16(3):581-584.
[20]Varadkar S, Surtees R. Glutaric aciduria type I and kynurenine pathway metabolites: Amodioed hypothesis. J Inherit Metab Dis.2004,27(6):835-842.
[21]Wajner M, Kolker S, Souza DO, et al. Modulation of glutamatergic and GABAergic neurotransmission in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2004,27(6):825-828.
[22]Rosa RB, Dalcin KB, Schmidt AL, et al. Evidence that glutaric acid reduces glutamate uptake by cerebral cortex of infant rats. Life Sci.2007, 81(25-26):1668-1676.
[23]Porciuncula LO, Emanuelli T, Tavares RG, et al. Glutaric acid stimulates glutamate binding and astrocytic uptake and inhibits vesicular glutamate uptake in forebrain from young rats. Neurochem Int.2004,45(7):1075-86.
[24]Sauer SW, Okun JG, Schwab MA, et al. Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency:a role for glutaryl-coenzyme A. J Biol Chem.2005, 280(23):21830-21836.
[25]Ferreira Gda C, Schuck PF, Viegas CM, et al. Energy metabolism is compromised in skeletal muscle of rats chronically-treated with glutaric acid. Metab Brain Dis.2007, 22(1):111-123.
[26]da C Ferreira G, Viegas CM, Schuck PF, et al. Glutaric acid moderately compromises energy metabolism in rat brain. Int J Dev Neurosci.2005,23(8):687-693.
[27]Latini A, Rodriguez M, Borba Rosa R, et al.3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats. Neuroscience.2005, 135(1):111一120.
[28]Ferreira GC, Tonin A, Schuck PF, et al. Evidence for a synergistic action of glutaric and 3-hydroxyglutaric acids disturbing rat brain energy metabolism. Int J Dev Neurosci.2007,25(6):391-398.
[29]Schuck PF, Tonin A, da Costa Ferreira G, et al. In vitro effect of quinolinic acid on energy metabolism in brain of young rats. Neurosci Res.2007,57(2):277-288.
[30]Lamp J, Keyser B, Koeller DM, et al. Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. J Biol Chem.2011, 286(20):17777-17784.
[31]Magni DV, Bruning CA, Gai BM, et al. m-Trifluoromethyl diphenyl diselenide attenuates glutaric acid-induced seizures and oxidative stress in rat pups: involvement of the y-aminobutyric acidergic system. J Neurosci Res.2012, 90(9):1723-31.
[32]Fernandez-Checa JC, Fernandez A, Morales A, et al. Oxidative stress and altered mitochondrial function in neurodegenerative diseases:lessons from mouse models. CNS Neurol Disord Drug Targets.2010,9(4):439-454.
[33]Latini A, Borba Rosa R, Scussiato K, et al.3-Hydroxyglutaric acid induces oxidative stress and decreases the antioxidant defenses in cerebral cortex of young rats. Brain Res.2002,956(2):367-373.
[34]de Oliveira Marques F, Hagen ME, Pederzolli CD, et al. Glutaric acid induces oxidative stress in brain of young rats. Brain Res.2003,964(1):153-158.
[35]Leipnitz G, Schumacher C, Scussiato K, et al. Quinolinic acid reduces the antioxidant defenses in cerebral cortex of young rats. Int J Dev Neurosci.2005, 23(8):695-701.
[36]Seminotti B, Amaral AU, da Rosa MS, et al. Disruption of brain redox homeostasis in glutaryl-CoA dehydrogenase deficient mice treated with high dietary lysine supplementation. Mol Genet Metab.2013,108(1):30-9.
[37]Latini A, Ferreira GC, Scussiato K, et al. Induction of oxidative stress by chronic and acute glutaric acid administration to rats. Cell Mol Neurobiol.2007, 27(4):423-438.
[38]Olivera S, Fernandez A, Latini A, et al. Astrocytic proliferation and mitochondrial dysfunction induced by accumulated glutaric acidemia I (GAI) metabolites: Possible implications for GAI pathogenesis. Neurobiol Dis.2008,32(3):528-534.
[39]Quincozes-Santos A, Rosa RB, Leipnitz G, et al. Induction of S100B secretion in C6 astroglial cells by the major metabolites accumulating in glutaric acidemia type 1. Metab Brain Dis.2010,25(2):191-198.
[40]Jafari P, Braissant O, Zavadakova P, et al. Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I. PLoS One.2013, 8(1):e53735.
[41]Olivera-Bravo S, Fernandez A, Sarlabos MN, et al. Neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia I. PLoS One.2011,6(6):e20831.
[42]Magni DV, Souza MA, Oliveira AP, et al. Lipopolysaccharide enhances glutaric acid-induced seizure susceptibility in rat pups:behavioral and electroencephalographic approach. Epilepsy Res.2011,93(2-3):138-148.
[43]Muhlhausen C, Ott N, Chalajour F, et al. Endothelial effects of 3-hydroxyglutaric acid:implications for glutaric aciduria type I. Pediatr Res.2006,59(2):196-202.
[44]Marti-Masso JF, Ruiz-Martinez J, Makarov V, et al. Exome sequencing identifies GCDH (glutaryl-CoA dehydrogenase) mutations as a cause of a progressive form of early-onset generalized dystonia. Hum Genet.2012,131(3):435-42.
[45]Carman KB, Aydogdu SD, Yakut A, et al. Glutaric aciduria type 1 presenting as subdural haematoma. J Paediatr Child Health.2012,48(8):712.
[46]Bishop FS, Liu JK, McCall TD, et al. Glutaric aciduria type 1 presenting as bilateral subdural hematomas mimicking nonaccidental trauma. J Neurosurg.2007, 106(3 Suppl Pediatrics):222-226.
[47]Heringer J, Boy SP, Ensenauer R, et al. Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol.2010,68(5):743-752.
[48]Kolker S, Garbade SF, Greenberg CR, et al. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res.2006,59(6):840-847.
[49]Lopez-Laso E, Garcia-Villoria J, Martin E, et al. Classic and late-onset neurological disease in two siblings with glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis.2007,30(6):979.
[50]McClelland VM, Bakalinova DB, Hendriksz C, et al. Glutaric aciduria type 1 presenting with epilepsy. Dev Med Child Neurol.2009,51(3):235-239.
[51]Renaud DL. Leukoencephalopathies associated with macrocephaly. Semin Neurol. 2012,32(1):34-41.
[52]Jamuar SS, Newton SA, Prabhu SP, et al. Rhabdomyolysis, acute renal failure, and cardiac arrest secondary to status dystonicus in a child with glutaric aciduria type I. Mol Genet Metab.2012,106(4):488-90.
[53]齐朝月,宋金青,肖江喜,等.戊二酸尿症I型患者的临床与脑磁共振成像特点.中国医刊.2006,41：26-29.
[54]Al-Dirbashi OY, Kolker S, Ng D, et al. Diagnosis of glutaric aciduria type 1 by measuring 3-hydroxyglutaric acid in dried urine spots by liquid chromatography tandem mass spectrometry. J Inherit Metab Dis.2011,34(1):173-180.
[55]韩连书,叶军,邱文娟,等.串联质谱联合气相色谱-质谱检测遗传代谢病.中华医学杂志.2008,88(30)：2122-2126.
[56]Mushimoto Y, Hasegawa Y, Kobayashi H, et al. Enzymatic evaluation of glutaric acidemia type 1 by an in vitro probe assay of acylcarnitine profiling using fibroblasts and electrospray ionization/tandem mass spectrometry (MS/MS). J Chromatogr B Analyt Technol Biomed Life Sci.2009,877(25):2648-2651.
[57]Greenberg CR, Prasad AN, Dilling LA, et al. Outcome of the three years of a DNA-based neonatal screening program for glutaric aciduria type I in Manitoba and Northwestern Ontaria, Canada. Mol Genet Metab.2002,75(1):70-78.
[58]Moore T, Le A, Cowan TM. An improved LC-MS/MS method for the detection of classic and low excretor glutaric acidemia type 1. J Inherit Metab Dis.2012, 35(3):431-5.
[59]娄燕,尹娜,陈凤琴,等.串联质谱技术选择性筛查遗传代谢病高危患儿552例初步分析.中国当代儿科杂志.2011,13(4)：296-299.
[60]Righini A, Fiori L, Parazzini C, et al. Early prenatal magnetic resonance imaging of glutaric aciduria type 1:case report. J Comput Assist Tomogr.2010,34(3):446-448.
[61]Ituk US, Allen TK, Habib AS. The peripartum management of a patient with glutaric aciduria type 1. J Clin Anesth.2013,25(2):141-5.
[62]Strauss KA, Brumbaugh J, Duffy A, et al. Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency:focus on cerebral amino acid influx. Mol Genet Metab.2011, 104(1-2):93-106.
[63]Tsiotou AG, Malisiova A, Bouzelos N, et al. The child with glutaric aciduria type I: anesthetic and perioperative management. J Anesth.2011,25(2):301-4.
[64]姚生,刘建国,于健,等.戊二酸尿症Ⅰ型患者的临床、影像与病理特点.中国神经免疫学和神经病学杂志.2008,15：15-18.