Eve Topf Center for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
Neurodegener Dis. 2010;7(1-3):108-11. doi: 10.1159/000285517. Epub 2010 Feb 18.
High-throughput gene-based platform studies in human postmortem substantia nigra (SN) from sporadic Parkinson's disease (PD) cases have revealed significant dysregulation of genes involved in biological processes linked to previously established neurodegenerative mechanisms in both sporadic and hereditary PD.
Our study aimed to develop a new genetic model of PD by modulating the expression of single genes that were found to be most significantly affected in SN of sporadic PD.
SN-derived cell line (SN4741 cells) was infected with short hairpin RNA lentiviruses carrying different gene-specific sequences.
Silencing of the E3 ligase ubiquitin SKP1A resulted in a decline in the expression of dopaminergic phenotypic markers together with progression into an aberrant cell cycle and death. Furthermore, added knockout of the dopamine-metabolizing enzyme aldehyde dehydrogenase, found almost absent in sporadic PD SN pars compacta, exacerbated the vulnerability of SKP1A-silenced neurons to MPP(+) and neurotrophin deprivation.
Future studies should focus on a careful consideration of crucial dopaminergic gene network interactions as emerged from human sporadic PD, which will serve as a basis for the development of a slowly progressive genetic animal model of sporadic PD, with the potential of evaluating drugs with 'disease-modifying activity'.
对散发性帕金森病（PD）病例死后黑质（SN）进行高通量基于基因的平台研究表明，涉及先前在散发性和遗传性 PD 中建立的神经退行性机制的生物过程的基因表达显著失调。
我们的研究旨在通过调节在散发性 PD SN 中受影响最显著的单个基因的表达，建立新的 PD 遗传模型。
SN 衍生的细胞系（SN4741 细胞）用携带不同基因特异性序列的短发夹 RNA 慢病毒感染。
E3 连接酶泛素 SKP1A 的沉默导致多巴胺能表型标志物的表达下降，同时进入异常细胞周期并死亡。此外，多巴胺代谢酶醛脱氢酶的添加敲除，在散发性 PD SN pars compacta 中几乎不存在，加剧了 SKP1A 沉默神经元对 MPP(+)和神经营养素剥夺的易感性。
未来的研究应重点关注从散发性 PD 患者中出现的关键多巴胺能基因网络相互作用，这将为开发具有“疾病修饰活性”的药物提供基础，以评估具有“疾病修饰活性”的药物。作为散发性 PD 遗传动物模型的缓慢进展的基础。
