Targeting mitochondrial complex I dependent NAD+ generation in Parkinson's Disease

Study Rationale: In two or three sentences, describe the background and scientific rationale for this project. Approximately 100 words Mitochondrial complex I inhibition is one of the major mechanisms in the development of Parkinson’s disease (PD). We have uncovered that decreasing mitochondrial complex I function results in diminished NAD+ which can trigger the production of a neurotoxic metabolite L-2hydroxyglutarate (L-2HG). Hypothesis: In one sentence, describe the question this study seeks to answer or the theory you hope to prove. Approximately 50 words We hypothesize that decreased NAD+ due to mitochondrial complex I dysfunction triggers the accumulation of neurotoxic metabolite L-2HG in dopaminergic neurons to cause PD-like pathology in mice. Study Design: In two or three sentences, in lay-oriented language, describe how you will carry out the project. Approximately 100 words The yeast NDI1 protein can rescue the loss of mitochondrial complex I NAD+ regeneration resulting in decreased L-2HG levels. The expression of L-2HGDH can also decrease L-2HG levels. We propose to conditionally overexpress NDI1 or L-2HGDH to