Microglia Dld-K127 lactylation promotes Parkinson’s disease via regulating the metabolism of lactate-pyruvate transformation

INTRODUCTION: Microglial activation represents a central pathological hallmark of Parkinson's disease (PD), characterized by a distinct metabolic reprogramming from oxidative phosphorylation toward glycolysis during pro-inflammatory activation. This metabolic shift drives lactate accumulation and subsequent protein lactylation, which has been increasingly implicated in PD development. However, the molecular mechanisms through which protein lactylation exerts its pathological effects remain largely unknown. OBJECTIVES: This study aimed to elucidate the mechanism by which lactate-derived protein lactylation contributes to PD pathogenesis. We sought to identify key protein targets of lactylation in PD models, elucidate the functional consequences of these modifications on cellular metabolism, and ultimately establish a comprehensive mechanism linking lactylation to dopamine (DA) neuronal degeneration. METHODS: We employed an integrated approach including comprehensive lactylome screening to identify modified proteins, functional enzymatic assays to determine the influence of specific lactylation events, and clinical correlation studies in human PD specimens to validate the pathological relevance of our findings across species. RESULTS: Following our initial observation of elevated lactate in PD mice, a subsequent finding revealed that up-regulation of lactylation was paralleled by enhanced microglial activation. Furthermore, endogenous lactate-derived lactylation was ultimately involved in the pathological process of PD. In addition, global lactylome revealed significant hyperlactylation of dihydrolipoyl dehydrogenase (Dld) at residues Lys127, Lys277, and Lys410. Mechanistically, Dld-K127 hyperlactylation inhibited pyruvate dehydrogenase (PDH) enzyme activity and promoted the metabolism of lactate-pyruvate transition, thereby accelerating DA neuronal degeneration. Meanwhile, Dld-K127 lactylation participate PD progression in p300 (lactylation writer)-dependent manner. Notably, clinical human specimens reveled that Dld-K127 lactylation, lactate and pyruvate production were increased in PD patients, accompanied with reduced PDH activity. CONCLUSION: Our finding defined a lactate-Dld-K127-pyruvate positive feedback loop that drove DA neuronal loss in "metabolism-epigenetic" level, positioning the disruption of this self-amplifying cycle as a viable therapeutic strategy for PD.