Evidence suggests that oxidative stress and mitochondrial dysfunction may be involved in neurodegeneration associated with Huntington's disease (HD). However, it is not clear whether oxidative damage to the mitochondrial DNA (mtDNA) and the repair of this damage are primary events in the neuropathogenesis of HD. Mitochondrial dysfunction and increased production of mitochondrial-generated reactive oxygen species (ROS) may contribute to neurodegeneration associated with HD. We hypothesize that mitochondrial dysfunction may occur as a consequence of increased levels of mtDNA damage and deficient repair. In this research proposal we will determine the relationship between mtDNA damage and repair and the neurodegeneration observed in HD. For this purpose we will use a transgenic mouse model of HD and a chemically-induced HD model using the mitochondrial toxin 3-nitropropionic acid (3-NPA).
The specific aims of this study are: 1) to determine brain regional differences in the levels of mitochondrial DNA damage and protein expression in a transgenic animal model of HD and if administration of superoxide dismutase (SOD) mimetics to the HD transgenic animals can attenuate oxidative stress and onset of the disease; 2) to develop a mouse neuronal cell model to study the relationship between mitochondrial DNA damage, loss of mitochondrial function, and cell death after exposure to 3-NPA and the effects resulting from administration of SOD mimetics; and 3) to determine the role of base excision repair genes in the repair of 3-NPA-induced mitochondrial DNA damage in mouse primary neuronal cell cultures. This study will lead to a better understanding of mitochondrial-linked neurodegeneration associated with liD, with particular emphasis in the role of mtDNA damage, repair of mtDNA damage, and mitochondrial dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS039408-09
Application #
7691234
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
9
Fiscal Year
2008
Total Cost
$421,198
Indirect Cost
Name
Universidad Central Del Caribe
Department
Type
DUNS #
090534694
City
Bayamon
State
PR
Country
United States
Zip Code
00960
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