Parkinson's disease (PD) is a progressive neurodegenerative disorder with no available disease-modifying therapies. Given their diverse health-promoting properties, probiotics have emerged as a potential neuroprotective strategy. Through screening in transgenic Caenorhabditis elegans (C. elegans) models of α-synuclein (α-syn)-induced PD, we identified the Escherichia coli (E. coli) strain E8 as a candidate that effectively suppressed dendritic degeneration and motor deficits. These neuroprotective improvements were attributed to the reduction of α-syn aggregation, which was mechanistically associated with E8's ability to promote autophagy. Metabolomic profiling further pinpointed 1-allylpiperazine (1-ALPP) as a bioactive metabolite responsible for rescuing PD-related impairments, which was sufficient to recapitulate the autophagy activation induced by E8. Subsequent mechanistic studies revealed that 1-ALPP activated autophagy through the AMPK/mTOR/HLH-30 pathway. Notably, 1-ALPP effectively inhibited α-syn fibrillogenesis and cytotoxicity in a dose-dependent manner, potentially via the inhibition of α-syn liquid-liquid phase separation (LLPS). Molecular simulations demonstrated that 1-ALPP binds to α-syn, thereby preventing the critical conformational changes required for fibril formation. Strikingly, the protective effects of E8 against PD phenotypes were intergenerationally inherited, persisting for two generations in an hpl-2-dependent manner.
