We have used a reverse genetic approach to investigate this question and created conditional knockout mice with reduced mtDNA expression in midbrain DA neurons. These mice have adult onset of slowly progressive, typical parkinsonian symptoms accompanied by progressive formation of intracellular inclusions and characteristic neuropathology. The inclusions are present in most DA neurons and contain both mitochondrial membranes and proteins. Our findings thus support an etiological role for respiratory chain dysfunction Parkinsons disease and suggest a novel mechanism for the formation of Lewy bodies.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2010
Total Cost
$199,631
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
Good, Cameron H; Hoffman, Alexander F; Hoffer, Barry J et al. (2011) Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease. FASEB J 25:1333-44
Harvey, Brandon K; Richie, Christopher T; Hoffer, Barry J et al. (2011) Transgenic animal models of neurodegeneration based on human genetic studies. J Neural Transm (Vienna) 118:27-45