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

ABSTRACT: 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 phosphoglycerate kinase 1 (PGK1), a gene in the PARK12 susceptibility locus, is rate limiting in neuronal glycolysis and that modestly increasing PGK1 expression boosts neuronal adenosine 5'-triphosphate production kinetics that is sufficient to suppress PARK20-driven synaptic dysfunction. We found that this 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 dopamine axons against metabolic lesions. These data support the notion that bioenergetic deficits may underpin PD-associated pathologies and point to improving neuronal adenosine 5'-triphosphate production kinetics as a promising path forward in PD therapeutics.

SUBMITTER: Kokotos AC

PROVIDER: S-EPMC11338267 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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

Kokotos Alexandros C AC Antoniazzi Aldana M AM Unda Santiago R SR Ko Myung Soo MS Park Daehun D Eliezer David D Kaplitt Michael G MG De Camilli Pietro P Ryan Timothy A TA

Science advances 20240821 34

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 phosphoglycerate kinase 1 (PGK1), a gene in the PARK12 susceptibility locus, is rate limiting in neuronal glycolysis and that modestly increasing PGK1 expression boosts neuronal adenosine 5'-triphosphate production kinetics that is sufficient to suppress PARK20-driven synaptic dysfuncti ...[more]

PMID: 39167658

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

Publications

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

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