Phosphoglycerate kinase is a central leverage point in Parkinson's Disease driven neuronal metabolic deficits

Although certain drivers of familial Parkinson’s Disease (PD) compromise mitochondrial integrity, whether metabolic deficits underly other idiopathic or genetic origins of PD is unclear. Here, we demonstrate that PGK1, a gene in the PARK12 susceptibility locus,  is rate limiting in neuronal glycolysis and that modestly increasing PGK1 expression significantly boosts  neuronal ATP production kinetics that is sufficient to suppress PARK20-driven synaptic dysfunction. We found that his activity enhancement depends on the molecular chaperone PARK7/DJ-1, whose loss of function significantly disrupts axonal bioenergetics. In-vivo, viral expression of PGK1 confers protection of striatal DA axons against metabolic lesions. These data support the notion that bioenergetic deficits may underpin PD associated pathologies and point to improving neuronal ATP production kinetics as a promising path forward in PD therapeutics.