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

Gastrointestinal (GI) disruptions, such as inflammatory bowel disease (IBD), are common prodromal symptoms of 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 symptoms in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male, but not female, mice promotes alpha-synuclein aggregation in the substantia nigra, elevated alpha-synuclein loads in microglia, loss of dopaminergic neurons, and motor impairment. This male bias in gene-environment interaction is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S, revealing that XY chromosomes, not testicular hormones, mediate the male bias in the gut-brain-driven risk for endophenotypes of PD. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by the accumulation of alpha-synuclein in the colon, increases in alpha-synuclein-positive macrophages in the colonic lamina propria, and elevations in alpha-synuclein loads within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD symptoms in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of alpha-synuclein in myeloid cells within the gut and brain.