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 #
5R01NS054022-08
Application #
8417683
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
2013-02-01
Budget End
2014-01-31
Support Year
8
Fiscal Year
2013
Total Cost
$331,418
Indirect Cost
$120,324
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Zhang, Yingjie; Yan, Jin; Yao, Tso-Pang (2017) Discovery of a fluorescent probe with HDAC6 selective inhibition. Eur J Med Chem 141:596-602
Nanduri, Priyaanka; Hao, Rui; Fitzpatrick, Thomas et al. (2015) Chaperone-mediated 26S proteasome remodeling facilitates free K63 ubiquitin chain production and aggresome clearance. J Biol Chem 290:9455-64
Zhang, Cheng-Wu; Hang, Liting; Yao, Tso-Pang et al. (2015) Parkin Regulation and Neurodegenerative Disorders. Front Aging Neurosci 7:248
Lee, Joo-Yong; Kawaguchi, Yoshiharu; Li, Ming et al. (2015) Uncoupling of Protein Aggregation and Neurodegeneration in a Mouse Amyotrophic Lateral Sclerosis Model. Neurodegener Dis 15:339-49
Norris, Kristi L; Hao, Rui; Chen, Liang-Fu et al. (2015) Convergence of Parkin, PINK1, and ?-Synuclein on Stress-induced Mitochondrial Morphological Remodeling. J Biol Chem 290:13862-74
Rao, Yanhua; Hao, Rui; Wang, Bin et al. (2014) A Mec17-Myosin II Effector Axis Coordinates Microtubule Acetylation and Actin Dynamics to Control Primary Cilium Biogenesis. PLoS One 9:e114087
Lee, Joo-Yong; Kapur, Meghan; Li, Ming et al. (2014) MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria. J Cell Sci 127:4954-63
Wang, Bin; Rao, Yan-Hua; Inoue, Makoto et al. (2014) Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production. Nat Commun 5:3479
Kim, Nam Chul; Tresse, Emilie; Kolaitis, Regina-Maria et al. (2013) VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron 78:65-80
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

Showing the most recent 10 out of 25 publications