UCLA

While Parkinson’s disease (PD) is a motor symptom disorder due to neurodegeneration of dopaminergic neurons and accumulation of Lewy bodies in the substantia nigra (SN), gastrointestinal dysfunctions are characteristic of prodromal PD. The most common monogenic mutation for PD lies in the gene leucine rich repeat kinase 2 (LRRK2), which harbors a mutation associated with IBD within the same locus. By studying the PD-causing mutation LRRK2 G2019S in transgenic (Tg) mice, we examined the effect that dextran sulfate sodium (DSS)-induced gut inflammation may have on the neuropathology of PD. This includes dopaminergic neuron loss, microglial and lysosomal activation, and alpha-synuclein (αSyn) aggregations in the SN. We found prodromal DSS-induced colitis exacerbates and accelerates neurodegeneration in LRRK2 G2019S Tg mice by 52 weeks of age. Prodromal colitis also promotes microglial activation and lysosomal formation. Interestingly, 23-week-old males showed increased αSyn aggregations in their microglia. Our data suggests that prodromal gut inflammation exacerbates the severity and onset of neurodegeneration and promotes neuroinflammation of PD driven by the LRRK2 G2019S mutation.