Abnormal accumulations of filamentous aggregates in neurons or glia are neuropathological hallmarks of many sporadic and hereditary neurodegenerative diseases. For example, Lewy bodies (LBs) formed by filamentous alpha-synuclein (a-syn) aggregates in neurons are characteristic of Parkinson's disease (PD), dementia with LBs (DLB) and an Alzheimer's disease (AD) subtype known as the LB variant of AD (LBVAD), while glial cytoplasmic inclusions (GCIs) composed of a-syn filaments are signature lesions of multiple system atrophy (MSA). The hypothesis that GCIs and LBs play a role in neurodegenerative disease was viewed with skepticism until it was shown that mutations in the a-syn gene cause familial PD, that a-syn is a major component of LBs and GCIs, and that mutant and wild type a-syn form filaments in vitro similar to those in LBs and GCIs. Moreover, it also was shown that beta- (b-syn) and gamma-synucleins (g-syn) accumulate in dystrophic processes, and that a-syn is selectively nitrated in GCIs of MSA as well as in a-syn lesions of all synucleinopathies. Thus, we hypothesize that the accumulations of filamentous a-syn aggregates are induced in part by oxidative/nitrative damage that plays an important role in the onset/progression of MSA. To test this hypothesis specifically in MSA, Aims 1-4 of this Project will analyze the potential contribution of oxidative/nitrative damage in a-syn filament formation and a-syn fibril aggregation into GCIs. In addition, Aims 5 and 6 will determine if/how GCIs compromise the viability of affected glial cells. Insights into the underlying mechanisms of synuclein pathologies and how they contribute to brain degeneration may lead to improved strategies for the diagnosis and treatment of MSA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS044233-02
Application #
7553782
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$196,537
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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