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
| Inoue, Keiichi; Rispoli, Joanne; Yang, Lichuan et al. (2013) Coordinate regulation of mature dopaminergic axon morphology by macroautophagy and the PTEN signaling pathway. PLoS Genet 9:e1003845 |
| MacLeod, David A; Rhinn, Herve; Kuwahara, Tomoki et al. (2013) RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 77:425-39 |
| Inoue, Keiichi; Rispoli, Joanne; Kaphzan, Hanoch et al. (2012) Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway. Mol Neurodegener 7:48 |
| Rhinn, Herve; Qiang, Liang; Yamashita, Toru et al. (2012) Alternative ?-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology. Nat Commun 3:1084 |
