Study Rationale: Three of the primary risk factors for Parkinson's disease (PD)—aging, environmental toxins and genetic mutations—all lead to impaired function of mitochondria, structures that generate the cell’s energy. We aim to investigate whether the NDI1 protein from yeast, which can compensate for impairment in the first component in the energy-generating pathway (called mitochondrial complex I), can alleviate PD-relevant symptoms in various models.
Hypothesis: We hypothesize the expression of the yeast NDI1 protein in dopamine neurons can bypass mitochondrial complex I dysfunction, thereby ameliorating motor symptoms and extending lifespan in PD models.
Study Design: We will use adeno-associated virus (AAV) to introduce yeast NDI1 protein into a variety of preclinical PD models, including mouse models and dopamine neurons derived from the stem cells of people with PD. We will then explore whether NDI1 mitigates mitochondrial complex I dysfunction and reduces pathology in these models.
Impact on Diagnosis/Treatment of Parkinson’s disease: Mitochondrial dysfunction is one of the core pathologies of PD. By investigating the ability of yeast NDI1 to rescue mitochondrial dysfunction, the research could lead to novel therapeutic strategies that target the mitochondrial deficits observed in PD.
Next Steps for Development: If successful, gene therapy using AAV or other approaches to deliver NDI1 would be attempted in non-human primate models of PD.