Sex Specific Effects of Environmental Toxin-Derived Alpha Synuclein on Enteric Neuronal-Epithelial Interactions

Parkinson's Disease (PD) is a neurodegenerative disorder with prodromal gastrointestinal (GI) issues often emerging decades before motor symptoms. Pathologically, PD can be driven by the accumulation of misfolded alpha synuclein (aSyn) protein in the brain and periphery, including the GI tract. Disease epidemiology differs by sex, with men twice as likely to develop PD. Women, however, experience faster disease progression, higher mortality, and more severe GI symptoms. Gut calcitonin gene-related peptide (CGRP) is a key regulator of intestinal contractions and visceral pain. The current study tests the hypothesis that sex differences in GI symptomatology in PD are the result of aSyn aggregation altering enteric CGRP signaling pathways.

To facilitate peripheral aSyn aggregation, the pesticide rotenone was administered intraperitoneally once daily for 2 weeks to male and female mice. Mice were sacrificed 2 weeks after the last rotenone injection, and immunohistochemistry was performed on sections of proximal colon.

Levels of aSyn were heightened in PGP9.5 immunoreactive myenteric plexus neurons, a subset of which were immunoreactive to CGRP and showed a similar increase in aSyn immunoreactivity in rotenone-treated mice. Female mice exhibited 153% more myenteric aSyn, 26% more apical CGRP immunoreactivity in the mucosa, and 66.7% more aSyn in apical CGRP⁺ fibers after rotenone when compared to males. Goblet cell numbers were diminished, but the individual cells were larger in the apical regions of crypts in the colons of rotenone-treated mice with no difference between males and females.

This study used a mouse model of PD to uncover sex-specific alterations in enteric neuronal and epithelial populations, underscoring the importance of considering sex as a biological variable while investigating prodromal GI symptoms.