Molekularbiologische Charakterisierung von Parkin: physiologische Funktion und pathologische Veränderungen beim juvenilen Parkinson-Syndrom

帕金森病是第二常见的神经退行性疾病，其特征是黑质致密部多巴胺能神经元的选择性丢失。虽然散发性帕金森病的病因仍是个谜，但至少已鉴定出8种单基因家系形式，包括编码α-突触核蛋白、parkin、泛素C末端水解酶L1(UCD-L1)和DJ-1的基因突变。Parkin基因突变，如错义、无义和移码突变、外显子缺失和倍增，广泛存在于各种常染色体隐性遗传性帕金森病(AR-PD)患者中，约占家族性PD病例的50%。根据目前的模型，致病的parkin突变损害了parkin作为E3泛素连接酶的功能，导致parkin底物的积累，最终可能损害多巴胺能神经元。然而，在多巴胺能神经元中，Parkin或其可能的底物都不是选择性表达的。该项目旨在探讨一个基本问题，即为什么Parkin的失活与多巴胺能神经元的选择性死亡有关。本课题组以前的研究结果表明，氧化应激和一些与AR-PD相关的突变导致了parkin的错误折叠和聚集。因此，我们计划分析哪些细胞因素在功能性parkin的生物合成中发挥作用，哪些机制导致parkin的失活，以及如何防止parkin的错误折叠从而失活。此外，我们将关注parkin在多巴胺能神经传递和多巴胺能细胞活力中可能的功能作用。这一方法也可能有助于理解散发性帕金森病的病理生理机制。

Parkinson's disease (PD), the second most common neurodegenerative disease, is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta. Whereas the etiology of sporadic PD is still enigmatic, at least 8 monogenic familial forms have been identified, including mutations in the genes encoding a-synuclein, parkin, ubiquitin C-terminal hydrolase L1 (UCD-L1) and DJ-1. Mutations in the parkin gene, such as missense, nonsense and frameshift mutations, exon deletions and multiplications, were found in a wide variety of patients suffering from autosomal recessive Parkinson's disease (AR-PD) and account for about 50% of all familial PD cases. According to the current model, pathogenic parkin mutations impair the function of parkin as an E3 ubiquitin ligase, leading to the accumulation of parkin substrates which ultimately might damage dopaminergic neurons. However, neither parkin nor its putative substrates are selectively expressed in dopaminergic neurons. This project is designed to approach the fundamental question, why the inactivation of parkin is associated with the selective demise of dopaminergic neurons. Previous results from our group indicated that oxidative stress and some mutations linked to AR-PD induce misfolding and aggregation of parkin. We therefore plan to analyze which cellular factors play a role in the biosynthesis of functional parkin, which mechanisms lead to the inactivation of parkin and how misfolding and thus inactivation of parkin may be prevented. Furthermore, we will focus on a possible functional role of parkin in dopaminergic neurotransmission and dopaminergic cell viability. This approach might also help to understand pathophysiological mechanisms implicated in the pathogenesis of sporadic PD.