Microglia Dld-K127 lactylation promotes Parkinson's disease via regulating the metabolism of lactate-pyruvate transformation - PubMed
7 hours ago
- #Parkinson's disease
- #Microglia
- #Lactylation
- Microglial activation is a key feature of Parkinson's disease (PD), involving a metabolic shift from oxidative phosphorylation to glycolysis.
- Lactate accumulation and protein lactylation are implicated in PD development, but the mechanisms are not fully understood.
- The study identifies dihydrolipoyl dehydrogenase (Dld) as a key target of lactylation at residues Lys127, Lys277, and Lys410 in PD models.
- Dld-K127 lactylation inhibits pyruvate dehydrogenase (PDH) activity, promoting lactate-pyruvate transformation and accelerating dopamine (DA) neuronal degeneration.
- The lactylation process is dependent on p300, a lactylation writer.
- Clinical human specimens show increased Dld-K127 lactylation, lactate, and pyruvate levels in PD patients, alongside reduced PDH activity.
- The study proposes a lactate-Dld-K127-pyruvate positive feedback loop driving DA neuronal loss at a 'metabolism-epigenetic' level.
- Disrupting this feedback loop is suggested as a potential therapeutic strategy for PD.