Abstract Jonas, EA Familial Parkinson’s disease (PD) protein DJ-1 mutations are linked to mitochondrial deficits and early onset PD but the exact mechanisms are unclear. We have found that mutations in DJ-1 and DJ-1 knock out increase mitochondrial uncoupling and hamper extension and branching of dopaminergic neuronal processes. The uncoupling is associated with abnormal ATP synthase efficiency and stoichiometry. The changes in ATP synthase are also associated with mitochondrial morphological changes including changes in cristae number, mitochondrial length and mitochondrial biogenesis. New protein synthesis is crucial to repair and maintain dopaminergic endings in the striatum and for normal dopamine release capacity. The activation of new protein synthesis is in response to cues such as growth factors or neuronal stimulation, but we hypothesize that new protein synthesis fails to occur when the stoichiometry of the ATP synthase is abnormal. In keeping with this, we find that protein synthesis levels are very low in patient cells and in DJ-1 KO mouse neurons. DJ-1 is bound to ATP synthase β subunit and ATP synthase β subunit mRNA. We therefore hypothesize that the mechanism of decreased growth and branching of DJ-1 deficient dopaminergic neurons is related to a lack of DJ-1 targeted, mitochondrially- regulated, mRNAs that are required for neuronal growth, repair and plasticity of dopaminergic cells. If we can restore the normal rate of protein synthesis downstream of DJ-1 in a spatially and temporally precise manner, we hypothesize we will slow neuronal ending degradation in DJ-1 mutant patients and preserve dopamine release capability. In keeping with this, we have now restored protein synthesis rates in patient cells by overexpression of ATP synthase β subunit. We now plan to determine if we can rescue low protein synthesis rates and neuronal growth in DJ-1 KO neurons, in neurons expressing mutant DJ-1 and in vivo in DJ-1 KO animals. We will do this by overexpression of ATP synthase β subunit by AAV (viral) delivery in neurons. In vivo, we will restore the normal coupling of mitochondria by crossing the DJ-1 KO mice with a low c-subunit leak KI mouse. We will restore the normal ATP synthase stoichiometry in vivo by crossing the DJ- 1 KO mouse with a mouse overexpressing ATP synthase β subunit. We hope to preserve neuronal endings in the striatum and prevent the onset of dysfunctional movement in the mice. Our observations suggest a connection between ATP synthase complex stoichiometry, protein synthesis rates and PD. Our plan comprises a promising new strategy to develop therapies for PD patients.