Modelling prodromal Parkinson’s disease: gastrointestinal pathology and early motor deficits in mice after transient rotenone exposure

Early gastrointestinal (GI) dysfunction is a hallmark feature of Parkinson’s disease (PD), yet models capturing prodromal gut and brain pathology in PD remain limited. Motivated by the increased PD risk associated with pesticide exposure, we monitored motor behavior, brain pathology, and GI structure and function over 9 months following 5 daily doses of rotenone in mice. Transient rotenone exposure induced significant nigrostriatal pathology, ∼48% loss of dopaminergic neurons and increased α-synuclein aggregation in the substantia nigra, without significant changes in gross motor function. Notably, we identified pronounced GI dysfunction including reduced colonic transit velocity, altered motility dynamics, and delayed whole-gut transit. These functional changes were accompanied by enteric dopaminergic neurodegeneration, increased colonic α-synuclein accumulation, increased colonic crypt depth, and goblet cell hyperplasia with elevated mucin content per goblet cell. The findings are consistent with prodromal PD, suggesting the utility of this model for investigating early disease mechanisms and intervention strategies.