Parkinson’s disease pathogenesis from G6PD deficiency
Loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates precedes the loss of dopaminergic neurons in Parkinson’s disease.
The researchers show that G6PD missense mutations increase the risk of PD diagnosis and that a-syn accumulation leads to G6PD dysfunction and deposition into Lewy bodies.
The authors 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.
This leads to loss of redox homeostasis (decreased nicotinamide adenine dinucleotide phosphate (NADP/H) and glutathione (GSH) levels) and dopamine oxidation that can be rescued pharmacologically by either N-acetylcysteine (NAC) or the G6PD agonist AG-1.
https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01529-8
