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.

Public Health Relevance

Several observations have linked Parkinson

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060876-02
Application #
7835524
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sieber, Beth-Anne
Project Start
2009-08-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$315,768
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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; Yang, Lichuan et al. (2013) Coordinate regulation of mature dopaminergic axon morphology by macroautophagy and the PTEN signaling pathway. PLoS Genet 9:e1003845
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