Elucidation of the regulation mechanisms that control the degradation of synaptic vesicle proteins represents a critical step towards our goal of understanding how synaptic function is regulated under physiologic conditions and how synaptic terminals become dysfunctional and degenerated in diseases. Synaptic vesicle proteins play a critical role in neurotransmitter release, and changes in the expression levels of synaptic vesicle proteins contribute to synaptic plasticity such as learning and memory. Furthermore, alterations in the expression levels of synaptic vesicle proteins are associated with a variety of neurodegenerative diseases and psychiatric disorders including drug addiction. Despite the importance of the regulation of synaptic vesicle protein levels in synaptic function and dysfunction, the molecular mechanisms underlying such regulation remain uncharacterized. On the other hand, the ubiquitin-proteasome proteolytic pathway has emerged as a major mechanism by which cells regulate the expression levels of specific proteins, and aberrations in the ubiquitin-proteasome pathway have been implicated in the pathogenesis of several neurodegenerative diseases. However, very little is known about neuronal protein substrates that are targeted by this pathway. The applicant hypothesizes that the ubiquitin-proteasome pathway targets synaptic vesicle proteins for degradation through specific E3 ubiquitin-protein ligases. In support of this hypothesis, our preliminary studies suggest that Siah-1 and Siah-2, a family of mammalian Seven in Absentia homologues, may act as E3 ubiquitin-protein ligases to regulate the degradation of synaptic vesicle protein synaptophysin. In this project, this hypothesis will be tested thoroughly.
The specific aims are to: 1) characterize Siah-mediated ubiquitination and degradation of synaptophysin at nerve terminals; 2) investigate the molecular mechanisms by which Siah-1 and Siah-2 regulate the ubiquitin-dependent degradation of synaptophysin; 3) identify additional synaptic targets of Siah proteins; 4) determine the distribution and subcellular localization of Siah proteins in the central nervous system; and 5) examine the role of Siah-mediated protein degradation in neuronal apoptosis. These studies should advance our understanding of protein degradation at synaptic terminals, and provide a basis for the development of therapeutic strategies for treating malfunctions of the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG021489-01
Application #
6556379
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Wise, Bradley C
Project Start
2003-02-01
Project End
2007-12-31
Budget Start
2003-02-01
Budget End
2003-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$342,000
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
Giles, Lisa M; Chen, Jue; Li, Lian et al. (2008) Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope. Hum Mol Genet 17:2712-22
Olzmann, J A; Li, L; Chin, L S (2008) Aggresome formation and neurodegenerative diseases: therapeutic implications. Curr Med Chem 15:47-60
Lee, James T; Wheeler, Tiffany C; Li, Lian et al. (2008) Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum Mol Genet 17:906-17
Pridgeon, Julia W; Olzmann, James A; Chin, Lih-Shen et al. (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5:e172
Olzmann, James A; Bordelon, Jill R; Muly, E Chris et al. (2007) Selective enrichment of DJ-1 protein in primate striatal neuronal processes: implications for Parkinson's disease. J Comp Neurol 500:585-99
Olzmann, James A; Li, Lian; Chudaev, Maksim V et al. (2007) Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol 178:1025-38
Kim, Bong Yoon; Olzmann, James A; Barsh, Gregory S et al. (2007) Spongiform neurodegeneration-associated E3 ligase Mahogunin ubiquitylates TSG101 and regulates endosomal trafficking. Mol Biol Cell 18:1129-42
Kirk, Elizabeth; Chin, Lih-Shen; Li, Lian (2006) GRIF1 binds Hrs and is a new regulator of endosomal trafficking. J Cell Sci 119:4689-701
Choi, Joungil; Sullards, M Cameron; Olzmann, James A et al. (2006) Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. J Biol Chem 281:10816-24

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