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Cited by 42Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingMitochondrial Function and Pathology

Phosphoglycerate kinase is a central leverage point in Parkinson’s disease–driven neuronal metabolic deficits

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Kokotos, Alexandros C., Antoniazzi, Aldana M., Unda, Santiago R., Ko, Myung Soo, Park, Daehun, Eliezer, David, Kaplitt, Michael G., De Camilli, Pietro +1 more·2024·Science Advances
DOI 10.1126/sciadv.adn6016PMC PMC11338267

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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.

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  • TZ-mediated activation of PGK1 inhibits synaptic vesicle recycling dysfunction at glutamatergic synapses induced by PARK20 mutation under hypometabolic condition.

    “TZ-mediated activation of PGK1 has previously shown to inhibit synaptic vesicle recycling dysfunction at glutamatergic synapses induced by PARK20 mutation under hypometabolic condition (Kokotos et al., 2024)”

    From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Kokotos et al., 2024

    The Results report that terazosin (TZ) improved synaptic endurance under low-glucose conditions, while PGK1 expression reversed the PARK20 synaptic vesicle recycling deficit. The PARK20 experiment used PGK1 expression, not TZ, and was conducted in 5 mM glucose; the paper does not report TZ rescuing PARK20 synapses under hypometabolic conditions. Page numbers were not provided in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Terazosin activates PGK1 at much lower concentration, resulting in enhanced production of ATP and pyruvate.

    “it also activates PGK1 at much lower concentration, resulting in enhanced productions of ATP and pyruvate (Fig. 4A) (Cai et al., 2019; Chen et al., 2015; Kokotos et al., 2024)”

    From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Kokotos et al., 2024

    The Introduction identifies terazosin as an off-target PGK1 activator, and Results (‘PGK1 expression accelerates local ATP production’) report improved nerve-terminal ATP production with terazosin. The copy does not establish activation at a ‘much lower concentration’ or show that terazosin enhances pyruvate production; it mentions pyruvate only as the end product of glycolysis. Page numbers were not available in the indexed passages. (LLM, conf=0.88)

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Authors
Kokotos, A. C., Antoniazzi, A. M., Unda, S. R., Ko, M. S., Park, D., Eliezer, D., Kaplitt, M. G., De Camilli, P., & Ryan, T. A.
Affiliations
  • Weill Cornell Medicine (US)
  • Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
  • Howard Hughes Medical Institute (US)
  • Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
Corresponding author
Ryan, Timothy A.
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-08-23
Volume
10
Issue
34
Pages
eadn6016-eadn6016
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.adn6016
PMC
PMC11338267
OpenAlex
W4401724314
Cited by
42
References
1
Citations by year
2026: 17 · 2025: 20 · 2024: 5
FWCI
10.60
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Michael J. Fox Foundation for Parkinson's Research (ASAP-000580, ASAP-020608, 020608)
  • Fondation pour la Recherche Médicale
  • National Institutes of Health (NS11739, NS036942)
  • National Institute of General Medical Sciences (R35GM136686)
  • National Institute of Neurological Disorders and Stroke (R37NS036942, R01NS036942)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
Parkinson's disease, PGK1, ATP production, molecular chaperones, striatum, synaptic dysfunction, neuronal metabolism, ATP synthase

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