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

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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.