The accumulation of protein aggregates and impaired mitochondrial function has emerged as a common denominator in neurodegenerative diseases. The long-term objective of this application is to elucidate the cellular machinery critical for the recognition and processing of toxic entities and its importance in the pathogenesis of neurodegenerative disease. We have discovered that the ubiquitin-binding deacetylase HDAC6 is a component of Lewy bodies and plays a critical role in the clearance of protein aggregate and impaired mitochondria. In mice, loss of HDAC6 results in accumulation of protein aggregates and neurodegeneration. We have identified HDAC6 as a critical component of quality control (QC) autophagy, which has recently emerged as the key machinery responsible for eliminating protein aggregates and damaged mitochondrial. We found that QC autophagy is functionally and molecularly distinct from the well characterized starvation-induced autophagy, suggesting a novel mechanism for the disposal of toxic entities linked to neurodegeneration. In this application, we propose to elucidate the molecular mechanism by which HDAC6 controls and connects the aggresomal pathway and QC autophagy, thereby facilitating the clearance of toxic protein aggregates. By delineating the molecular composition and regulation of QC autophagy, we wish to gain novel insight into how cells process and dispose toxic protein aggregates and the mechanistic basis for the progression of neurodegenerative disease.

Public Health Relevance

The accumulation of toxic protein aggregates and impaired mitochondrial function has emerged as a common denominator in neurodegenerative diseases. By characterizing the mechanism and protein machinery that eliminate toxic protein aggregates and damaged mitochondria, we hope to identify new avenues for developing novel therapeutic approaches for treating neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054022-07
Application #
8247696
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2006-01-04
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
7
Fiscal Year
2012
Total Cost
$343,438
Indirect Cost
$124,688
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Hao, Rui; Nanduri, Priyaanka; Rao, Yanhua et al. (2013) Proteasomes activate aggresome disassembly and clearance by producing unanchored ubiquitin chains. Mol Cell 51:819-28
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Lee, Joo-Yong; Yao, Tso-Pang (2010) Quality control autophagy: a joint effort of ubiquitin, protein deacetylase and actin cytoskeleton. Autophagy 6:555-7
Norris, Kristi L; Lee, Joo-Yong; Yao, Tso-Pang (2009) Acetylation goes global: the emergence of acetylation biology. Sci Signal 2:pe76

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