Several observations have linked neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease with altered intracellular protein degradation (1). Recently, autophagy mechanisms leading to lysosomal-mediated protein degradation have come into focus. Autophagy is an essential mechanism of protein degradation that is induced in the context of starvation and other stressors, and is a prominent feature in brain pathology in neurodegenerative diseases (3, 4), likely representing defects in the autophagy-lysosome pathway (5). Furthermore, mutations in lysosomal genes have been found to underlie rare familial inherited forms of Parkinsonism (6) and associated with common sporadic PD(3). Key questions exist: i. Do autophagy defects recapitulate aspects of neurodegenerative disorders? ii. By what mechanism does altered autophagy in mDNs lead to pathological and morphological changes? We hypothesize, based on preliminary data, that: i. Autophagy plays a central role in regulating the survival and morphology of mDNs, and deficiency of autophagy recapitulates key aspects of neurodegenerative pathology, including accumulation of disease-associated proteins. ii. A novel mechanism by which autophagy defects lead to pathology is through direct (but non- canonical) downstream modification of the PI3K/PTEN/AKT/GSK3beta/Tau signaling pathway;this relates specifically to altered accumulation of signaling pathway components. iii. The altered PI3K/PTEN/AKT/GSK3beta/Tau pathway signaling plays a causal role in the phenotypes associated with autophagy deficiency.
Several observations have linked Parkinson
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