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

Publication Type	Preprint
Authors	Kokotos A, Antoniazzi A, Unda S, Ko M, Park D, Eliezer D, Kaplitt M, Camilli P, Ryan T
Journal	bioRxiv
Date Published	10/10/2023
ISSN	2692-8205
Abstract	Phosphoglycerate kinase 1 (PGK1), the first ATP producing glycolytic enzyme, has emerged as a therapeutic target for Parkinson's 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.
DOI	10.1101/2023.10.10.561760
PubMed ID	37873141
PubMed Central ID	PMC10592794