Phosphoglycerate kinase 1 is a central leverage point in Parkinson's disease driven neuronal metabolic deficits

Abstract

Phosphoglycerate kinase 1 (PGK1), the first ATP producing glycolytic enzyme, has emerged as a therapeutic target for Parkinsons Disease (PD), since a potential enhancer of its activity was reported to significantly lower PD risk. We carried out a suppressor screen of hypometabolic synaptic deficits and demonstrated that PGK1 is a rate limiting enzyme in nerve terminal ATP production. Increasing PGK1 expression in mid-brain dopamine neurons protected against hydroxy-dopamine driven striatal dopamine nerve terminal dysfunction in-vivo and modest changes in PGK1 activity dramatically suppressed hypometabolic synapse dysfunction in vitro. Furthermore, PGK1 is cross-regulated by PARK7 (DJ-1), a PD associated molecular chaperone, and synaptic deficits driven by PARK20 (Synaptojanin-1) can be reversed by increasing local synaptic PGK1 activity. These data indicate that nerve terminal bioenergetic deficits may underly a spectrum of PD susceptibilities and the identification of PGK1 as the limiting enzyme in axonal glycolysis provides a mechanistic underpinning for therapeutic protection. O_LISuppressor screen identifies PGK1 as the rate limiting enzyme in axon metabolism C_LIO_LIPGK1 expression in-vivo protects against striatal dopaminergic axon degeneration C_LIO_LILoss of DJ-1 impairs axonal ATP production C_LIO_LIPGK1 function is regulated by PARK7/DJ-1, and can reverse PARK20 synaptic deficits C_LI