Microglial Dld-K127 lactylation regulates the metabolism of lactate-pyruvate transition to accelerate Parkinson's disease

Microglial activation is a central pathological hallmark of Parkinson's disease (PD). Microglia switch metabolism from oxidative phosphorylation (OXPHOS) toward glycolysis upon pro-inflammatory activation. Glycolysis-drived lactylate accumulation contributed to the development and progression of PD. However, the underlying mechanisms remain unclear. Here, after first detecting elevated lactate in PD mice, we also observed that up-regulated lactylation was accompanied by increased microglia activation. Furthermore, endogenous lactate-derived lactylation was ultimately involved in the pathological process of PD. Next, the global lactylome revealed that dihydrolipoyl dehydrogenase (Dld) at Lys 127, 277, 410 site were elevated. Further functional verification studies showed that hyperlactylation of Dld at Lys 127 inhibited pyruvate dehydrogenase (PDH) enzyme activity and promoted the metabolism of lactate-pyruvate transition, ultimately alleviating dopamine (DA) neuronal damage. Meanwhile, p300 (lactylation writer) was increased in PD mice and pharmacologic inhibition of p300 could attenuate PD. Together, this work demonstrated a lactate/Dld-K127/pyruvate positive feedback loop that drived DA neuronal damage in “metabolism - epigenetic” level and suggested that suppressing this vicious feedback circle as a promising therapeutic target for PD.