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 <i>Caenorhabditis elegans</i> 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(definition), 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.