siRNA-based therapy in models of Parkinson disease

Coordinator:		Prof. Dr. Günter U. Höglinger
Institution:		Translational Neurodegeneration, Technische Universität München
Homepage:		www.neurokopfzentrum.med.tum.de/neurologie

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. There is strong interest in the development of new therapeutic approaches to stop disease progression. Therefore, a deeper understanding of the mechanisms leading to neuronal dysfunction and death is urgently required. Alpha-synuclein is the main component of intraneuronal proteinaceous inclusions, termed Lewy bodies, in diseased neurons in sporadic PD patients. Five known mutations of alpha-synuclein (A30P, A53T, E46K, H50Q, G51D) and multiplication of the alpha-synuclein gene lead to rare familial forms of PD with clinical characteristics similar to sporadic PD. The molecular mechanism initiated by alpha-synuclein and leading to neurotoxicity is incompletely understood. Research into this question has been limited by the availability of adequate experimental models so far.

To overcome the past limitations, we have developed a new model of wild-type alpha-synuclein-induced neuronal cell death in human post-mitotic, dopaminergic neurons. The RNA interference (RNAi) technique is an extremely powerful tool for probing gene function. It derives its utility from the ability of small double-stranded RNAs [small interfering RNAs (siRNAs)] to specifically silence genes containing sequences identical to those in the siRNAs. siRNA can be administered in vitro and in vivo and high throughput screens using siRNA libraries allow systematically interrogating whole genomes for proteins involved in cellular processes. We used the RNAi method in a genome-wide high-throughput screen and identified key components of the molecular cascade leading to neuronal cell death in cell culture models of Parkinson disease. In future work, the identified genes will serve as candidate targets, which may serve as for the development of neuroprotective interventions for human patients.