Gut microbiota-derived succinate links proteostasis collapse to α-synuclein pathology and aging

The gut microbiome profoundly influences brain health, yet the specific microbial metabolites and mechanisms contributing to Parkinson's disease pathology remain poorly defined. Using the Caenorhabditis elegans model expressing human α-synuclein, we systematically tested key microbial fermentation products and identified succinate as a potent driver of pathology. Succinate exposure markedly increased α-synuclein aggregation, disrupted proteostasis, and compromised mitochondrial function - manifesting as oxidative stress, reduced mitochondrial content, and attenuated UPR^mt. These cellular defects led to dopaminergic neurodegeneration, locomotory impairments, and reduced lifespan, establishing succinate as a pro-neurodegenerative and pro-aging metabolite. Transcriptomic and genetic analyses revealed the involvement of nutrient-sensing pathways, prominently mTORC1, in promoting proteotoxic stress. Together, these findings highlight a direct link between microbial metabolism, proteostasis collapse, and neurodegeneration, establishing succinate as an active modulator of aging. Targeting succinate signaling mechanisms may therefore represent a tractable strategy for microbiome-based interventions in Parkinson's disease and age-associated neurodegeneration.