Sex-dependent interactions between prodromal intestinal inflammation and LRRK2 G2019S in mice promote endophenotypes of Parkinson’s disease

Abstract Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinson’s disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.