IDENTIFICATION OF GENES IMPACTING DOPAMINERGIC NEURON DEGENERATION VIA GUT-DERIVED METHYLGLYOXAL

Parkinson’s disease (PD) is increasingly recognized as a disorder shaped by gut–brain interactions, yet the microbial genes and metabolites linking dysbiosis to dopaminergic neurodegeneration remain poorly defined. Here, we identify the Escherichia coli (E. coli) histone-like nucleoid structuring protein hns and its associated metabolite methylglyoxal (MG) as microbial factors contributing to dopaminergic neurodegeneration. Deletion of hns in E. coli markedly attenuated dopaminergic neuron loss in Caenorhabditis elegans PD models induced by either 6-hydroxydopamine or α-synuclein overexpression. This neuroprotective effect was abolished by exogenous MG, indicating MG-dependent regulation. Transcriptomic reanalysis further identified the neuronal guidance gene rig-5 as a critical mediator of this effect, as RNAi-mediated knockdown of rig-5 eliminated dopaminergic neuron rescue. Extending these findings to mammals, colonization of mice with Δhns E. coli increased Lsamp, the mammalian ortholog of rig-5, in the substantia nigra. Consistently, LSAMP expression was directly suppressed by MG in human neuroblastoma cells. Notably, analyses of PD patient datasets revealed concordant alterations along this axis. Fecal metagenomic profiling showed that hns was scarcely detectable in healthy controls but significantly enriched in PD patients, while transcriptomic analysis demonstrated that LSAMP was significantly downregulated in the substantia nigra of PD patients. Together, these results define a conserved gut microbial hns–MG–rig-5/LSAMP axis that links bacterial metabolism to host neuronal gene regulation and dopaminergic neurodegeneration in PD.