The role of autophagy in the etiopathogenesis of Parkinson's disease

• Antragsteller: Dr. Martin Lenard Lachenmayer
• Fachliche Zuordnung: Molekulare und zelluläre Neurologie und Neuropathologie
• Förderung: Förderung von 2008 bis 2011
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 82122518

Toxic accumulation of alpha-synuclein, dysfunctional protein clearance and oxidative stress may collaboratively lead to the degeneration of midbrain dopaminergic (DA) neurons in the pathological process of Parkinson`s Disease. Autophagy is a regulated lysosomal pathway that has been implicated in the clearance of protein aggregates. The emerging evidence indicates that autophagy is involved in the catabolism of alpha-synuclein. Autophagy-lysosomal function declines over age in human brain and has been proposed to contribute in part to the increase of oxidative stress. The hypothesis is that autophagy prevents toxic accumulation of disease proteins and build-up of oxidative stress in neurons. The aim of this proposal is to test whether autophagy is required for the clearance of alpha-synuclein, prevention of oxidative stress in DA neurons and protection against the degeneration of DA neurons. Conditional knock-out (cKO) mice in which an essential autophagy gene Atg7 is deleted specifically in DA neurons, and the same cKO mice but expressing human alpha-SynA53T will be generated and characterized. The applicant will test in the Atg7-deficient DA neurons whether endogenous WT alpha-synuclein and human alpha-synA53T are deposited into Lewy body-like inclusions, separately. Additionally, the effect of inactivation of autophagy on oxidative stress level, striatal dopamine content and DA neuron degeneration will be investigated.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: USA
• Gastgeber: Professor Dr. Yue Zhenyu