Mitochondrial dysfunction and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are the features of Parkinson's disease (PD). We have identified a multifunctional member of the short chain dehydrogenase reductase family, termed amyloid-beta binding alcohol dehydrogenase (ABAD), and also known as L-3-hydroxyacyl-CoA dehydrogenase (HADH), 17-beta-hydroxysteroid dehydrogenase type 10, and 3-methyl-2-hydroxybutyryl-CoA dehydrogeanse (MHBD). In neurons, ABAD is localized to the mitochondrial matrix. ABAD expression is diminished in the murine MPTP model and in the pars substantia nigra of PD patients. A parallel reduction in ABAD/MHBD enzyme activity was observed in PD-affected regions and in purified ABAD protein treated with MPTP. Transgenic mice with neuronal overexpression of ABAD (Tg ABAD) displayed resistance to neuronal apoptosis/cell loss following administration of MPTP. Furthermore, purified mitochondria from brains of Tg ABAD mice exposed to MPP+ demonstrated enhanced oxygen consumption and less of a defect in complex I, compared with mitochondria from nonTg littermates. These data lead us to propose that ABAD exerts a cytoprotective effect in the setting of mitochondrial stress relevant to PD. Our application will seek to assess mechanisms through which ABAD has this beneficial effect. focusing on its enzyme activity and ABAD-cypD interaction. The results of our studies should provide information as to whether enhancing ABAD activity is a potential future strategy for treatment of PD.