The long-term objective of this proposal is to elucidate the cellular machinery critical for the processing of toxic protein aggregates and its role in the pathogenesis of neurodegenerative disease. The cocentration of protein aggregates to a specialized inclusion body, the aggresome, has emerged as a critical cellular response to the pathological accumulation of misfolded proteins. The clinical relevance of aggresomes is implicated by its striking similarity to Lewy bodies, the pathohistological hallmark of Parkinson's and other neurodegenerative diseases. We have discoverd that the microtubule-associated deacetylase HDAC6 is a componet of Lewy bodies and plays a critical role in aggresome formation. Loss of HDAC6 results in a failure in aggresome formation and pronounced cell death in response to misfolded protein accumulation. We hypothesize that HDAC6 protects neurons by recognizing and facilitating the transport of ubiquitinated protein aggregates to aggresomes/Lewy bodies, thereby preventing neurodegeneration caused by toxic protein aggregates. We propose:
Aim 1. To delineate the function of the HDAC6 complex in ubiquitin-dependent misfolded protein processing. We will charaterize the ubiquitin-binding activity of HDAC6 complex and determine the nature and functions of poly-ubiquitin modification in misfolded protein processing and aggresome formation .
Aim 2. To characterize the role of HDAC6-mediated deacetylation in misfolded protein processing and aggresome formation. We will determine how protein acetylation regulates the function of the misfolded- protein ubiquitin ligase CHIP and the transport of misfolded proteins by the microtubule network.
Aim 3. To characterize the role of HDAC6 in the pathogenesis of Parkinson's disease. We will determinie whether HDAC6 knockout mice are defective in forming Lewy bodies and more susceptible to neurodegeneration in response to Parkinsonism-inducing mutant a-synuclein expression. The accumulation of toxic protein aggregates has emerged as a common cause of neurodegenerative diseases. By characterizing the mechanism and protein machinery that eliminate toxic protein aggregates, 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 #
5R01NS054022-05
Application #
7751343
Study Section
Special Emphasis Panel (ZRG1-CDIN-D (01))
Program Officer
Sutherland, Margaret L
Project Start
2006-01-04
Project End
2011-03-31
Budget Start
2010-01-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$337,412
Indirect Cost
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
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
Lee, Joo-Yong; Koga, Hiroshi; Kawaguchi, Yoshiharu et al. (2010) HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 29:969-80

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