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

帕金森病（Parkinson's disease，PD）是第二常见的神经退行性疾病，其特征在于黑质背侧部多巴胺能神经元的选择性丧失。尽管散发性PD的病因仍然是谜，但已经鉴定出至少8种单基因家族形式，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的基因中的突变。parkin基因的突变，如错义突变、无义突变和移码突变、外显子缺失和倍增，在各种常染色体隐性遗传帕金森病（AR-PD）患者中发现，约占所有家族性PD病例的50%。根据目前的模型，致病性帕金突变损害了帕金作为E3泛素连接酶的功能，导致帕金底物的积累，最终可能损害多巴胺能神经元。然而，无论是帕金或其假定的底物选择性地表达多巴胺能神经元。这个项目的目的是接近的基本问题，为什么帕金的失活与多巴胺能神经元的选择性死亡。我们小组的先前结果表明，氧化应激和与AR-PD相关的一些突变诱导parkin的错误折叠和聚集。因此，我们计划分析哪些细胞因子在功能性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的错误折叠和失活。此外，我们将集中在多巴胺能神经传递和多巴胺能细胞活力的帕金可能的功能作用。这种方法也可能有助于了解参与散发性PD发病机制的病理生理机制。

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.