G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis

Loss of dopaminergic neurons in Parkinson's disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels, resulting in DA oxidation and decreased total DA levels. We find that α-syn anchors the PPP enzyme G6PD to synaptic vesicles via the α-syn C terminus and that this interaction is lost in PD. Furthermore, G6PD clinical mutations are associated with PD diagnosis, and G6PD deletion phenocopies PD pathology. Finally, we show that restoring NADPH or GSH levels through genetic and pharmacological intervention blocks DA oxidation and rescues steady-state DA levels, identifying G6PD as a pharmacological target against PD.

Authors

Institutions

Publication Details

Journal
Cell Reports
Published
2025-01-01
DOI
https://doi.org/10.1016/j.celrep.2024.115178
Citations
18
Primary Topic
Neonatal Health and Biochemistry
Type
article
Field-Weighted Citation Impact
62.89
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis

Era Taoufik, Scott D. Ryan, Joel C. Watts, Elissavet-Kalliopi Akrioti et al.
18 citations
Cell Reports
Neonatal Health and Biochemistry
62.89
article

G6PD deficiency triggers dopamine loss and the initiation of Parkinson’s disease pathogenesis

Era Taoufik, Scott D. Ryan, Joel C. Watts, Elissavet-Kalliopi Akrioti, Raphaella W. L. So, Rekha G. Panchal, Tariq A. Akhtar, Eric Soubeyrand, Erica Stuart, Carla Coackley, Omid Haji‐Ghassemi, Morgan G. Stykel, Ping Lu, Jessil Joseph, Shehani V. Siripala, Suelen Camargo, Sharanya Thevasenan, Gerardo Balderas Figueroa
article en
18 citations

Abstract

Loss of dopaminergic neurons in Parkinson's disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels, resulting in DA oxidation and decreased total DA levels. We find that α-syn anchors the PPP enzyme G6PD to synaptic vesicles via the α-syn C terminus and that this interaction is lost in PD. Furthermore, G6PD clinical mutations are associated with PD diagnosis, and G6PD deletion phenocopies PD pathology. Finally, we show that restoring NADPH or GSH levels through genetic and pharmacological intervention blocks DA oxidation and rescues steady-state DA levels, identifying G6PD as a pharmacological target against PD.

Cell ReportsVol. 44(1)
University of Calgary (CA), University of Toronto (CA), Occupational Cancer Research Centre (CA), Pasteur Hellenic Institute (GR), University of Guelph (CA)
Openalex Percentile: Top 0%
Neonatal Health and Biochemistry
62.89
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.