Over the last several years, macroautophagy has been implicated in a wide array of neurodegenerative disorders from the aggregation prone disorder, Huntington's disease to the lysosomal storage disorders, Neiman-Pick Type C. Despite its prevalence however, macroautophagy is still poorly understood, making it difficult to define how it contributes towards pathogenesis. Perhaps unsurprisingly, in different disorders, macroautophagy has been considered both as a potentially causative and potentially ameliorative element in disease progression. If we are to target this complex degradative pathway for therapeutics, we need to better define the autophagic process in a means we can apply it towards the brain. In this grant submission, we propose to gain new insights into macroautophagy by focusing on the key organelle involved: the autophagic vacuole (AV). Defined as an onion-like multilamellar vesicle that is positive for the marker MAP1LC3 (a mammalian homologue of ATG8), the formation and maturation of this structure is at the heart of the autophagic process and is by far the least understood. Using a novel approach which we have developed that can isolate specific populations of AV for proteomic and lipid-based analyses, we will: 1) characterize AVs from neuronal cells and brain;2) compare and contrast MAP1LC3- labeled AVs from vesicles labeled with the other four ATG8 mammalian homologues;and 3) use functional cell based assays to further define how the various ATG8- proteomes impact macroautophagy.

Public Health Relevance

Macroautophagy is a poorly understood process that is important for allowing cells, such as neurons to get rid of proteins that no longer function. Interestingly, this process has been implicated to be at the heart of many neurodegenerative diseases such as Huntington's disease, Parkinson's disease, Alzheimer's disease, many lysosomal storage diseases and others. Here we propose to study macroautophagy as it pertains to the brain so that we can use this information to design effective treatment for these many diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063973-02
Application #
7692985
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gwinn, Katrina
Project Start
2008-09-30
Project End
2013-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$352,188
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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