Although Parkinson's disease (PD) has been known for nearly two centuries, the molecular mechanisms underlying the pathogenesis of PD remain poorly understood, and currently there is no cure to stop the progression of this devastating disease. Molecular characterization of the gene products underlying the rare familial forms of PD can help delineate the pathogenic pathways associated with neurodegeneration in the common sporadic forms of PD. Recently, deletion and missense mutations in DJ-1 were identified as the genetic defects for an early-onset, autosomal recessive form of familial PD. Furthermore, DJ-1 was found to localize within a subset of pathological tau inclusions in Picks disease, Alzheimer's disease, Lewy body dementia, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism linked to chromosome 17. However, little is presently known about the biological function of DJ-1 and how DJ-1 mutations cause neurodegeneration. In this project, the applicant will use a combination of biochemical, cell biological, proteomic, and molecular genetic approaches to address the following questions: What is the biochemical function of DJ-1? Does DJ-1 act in a similar cellular pathway as alpha-synuclein, parkin and UCH-L1 or in a different pathway distinct from these other familial PD genes? How do PD-linked missense mutations affect the structure and function of DJ-1 and neuronal survival? Is DJ-1 irreversibly oxidized in idiopathic PD? If so, does oxidative damage to DJ-1 contribute to the pathogenesis of sporadic PD in a manner similar to DJ-1 genetic mutations in causing familial PD? Answers to these questions will not only advance our knowledge about the normal function of DJ-1 in neuronal physiology, but should also yield novel insights into the molecular mechanism by which DJ-1 mutations lead to neurodegeneration. Completion of the proposed project should advance our understanding of PD pathogenesis, and accelerate the efforts to discover curative therapies for PD and related neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050650-03
Application #
7385120
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Sieber, Beth-Anne
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
3
Fiscal Year
2008
Total Cost
$334,267
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lee, Samuel M; Chin, Lih-Shen; Li, Lian (2012) Therapeutic implications of protein homeostasis in demyelinating peripheral neuropathies. Expert Rev Neurother 12:1041-3
Lee, Samuel M; Chin, Lih-Shen; Li, Lian (2012) Protein misfolding and clearance in demyelinating peripheral neuropathies: Therapeutic implications. Commun Integr Biol 5:107-10
Lee, Samuel M; Olzmann, James A; Chin, Lih-Shen et al. (2011) Mutations associated with Charcot-Marie-Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome-autophagy pathways. J Cell Sci 124:3319-31
Sha, Di; Chin, Lih-Shen; Li, Lian (2010) Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum Mol Genet 19:352-63
Chen, Jue; Li, Lian; Chin, Lih-Shen (2010) Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage. Hum Mol Genet 19:2395-408
Chin, Lih-Shen; Olzmann, James A; Li, Lian (2010) Parkin-mediated ubiquitin signalling in aggresome formation and autophagy. Biochem Soc Trans 38:144-9
Giles, Lisa M; Li, Lian; Chin, Lih-Shen (2009) Printor, a novel torsinA-interacting protein implicated in dystonia pathogenesis. J Biol Chem 284:21765-75
Giles, Lisa M; Li, Lian; Chin, Lih-Shen (2009) TorsinA protein degradation and autophagy in DYT1 dystonia. Autophagy 5:82-4
Pridgeon, Julia W; Webber, Elizabeth A; Sha, Di et al. (2009) Proteomic analysis reveals Hrs ubiquitin-interacting motif-mediated ubiquitin signaling in multiple cellular processes. FEBS J 276:118-31
Whatley, Brandi R; Li, Lian; Chin, Lih-Shen (2008) The ubiquitin-proteasome system in spongiform degenerative disorders. Biochim Biophys Acta 1782:700-12

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