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bioRxiv · 10.1101/2024.11.27.625701

Sex specific effects of environmental toxin-derived alpha synuclein on enteric neuronal-epithelial interactions

Templeton, H. N.·Ehrlich, A. T.·Schwerdtfeger, L. A.·Sheng, J. A.·Tjalkens, R. B.·Tobet, S. A.
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Abstract

BackgroundParkinsons Disease (PD) is a neurodegenerative disorder with prodromal gastrointestinal (GI) issues often emerging decades before motor symptoms. Pathologically, PD can be driven by 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 symptomology in PD are the result of aSyn aggregation altering enteric CGRP signaling pathways. MethodsTo facilitate peripheral aSyn aggregation, the pesticide rotenone was administered intraperitoneally once daily for two weeks to male and female mice. Mice were sacrificed two weeks after the last rotenone injection and immunohistochemistry was performed on sections of proximal colon. Key ResultsLevels of aSyn were heightened in myenteric plexus neurons and a subset of neurons immunoreactive to CGRP in rotenone treated mice. Female mice exhibited 153% more myenteric aSyn, 26% more apical CGRP immunoreactivity, 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. ConclusionsThis 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=143 HEIGHT=200 SRC="FIGDIR/small/625701v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@19a6dforg.highwire.dtl.DTLVardef@1a9324org.highwire.dtl.DTLVardef@b253d4org.highwire.dtl.DTLVardef@19d89cf_HPS_FORMAT_FIGEXP M_FIG C_FIG KEY POINTSO_LIMouse model of Parkinsons Disease (PD) was used to investigate sex specific impact of enteric alpha synuclein (aSyn) on colonic goblet cells and CGRP+ neurons and fibers. C_LIO_LISex specific alterations in intestinal neuronal and epithelial signaling pathways in response to aSyn provides insight into sex differences in PD etiology and prodromal gastrointestinal symptoms. C_LI

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Templeton, H. N., Ehrlich, A. T., Schwerdtfeger, L. A., Sheng, J. A., Tjalkens, R. B., Tobet, S. A.. 2024-12-03. Sex specific effects of environmental toxin-derived alpha synuclein on enteric neuronal-epithelial interactions. https://doi.org/10.1101/2024.11.27.625701

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