A041 Enteric nervous system (ENS) alterations in Huntington’s disease (HD): hints on neglected phenotypes

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While central nervous system symptoms in HD are well-documented, less attention has been given to peripheral symptoms like unintended weight-loss1 2 and gastrointestinal (GI) dysfunction,3 4 which greatly affect patients‘ life quality. Composed by more than a dozen of different neuronal types, the ENS controls GI motility, secretions, digestion, peristalsis.5 6 Different studies in neurodegenerative diseases,7–9 report that alterations in the ENS can lead to GI changes, including neuroinflammation.10 11 While experiments on HD mice initially established a correlation between weight loss and GI dysfunction,12–14 systematic studies are still lacking. Our study aims to provide details about GI changes related to ENS alterations, using WT and Htt knock-in (zQ175) mice that accurately mirror HD genetics.15 We examined ENS structure through immunofluorescence, revealing increased GFAP signals in the colon at 15 months of age, confirmed by wester-blot analysis. Inspection of gene-expression changes and morphological alteration of ENS primary culture from young mice, revealed again a higher level of glial cells in HD models, correlating with an altered cellular morphology. On the mechanistic point of view, because BDNF secretion has been associated to astrocytes16 and its transport resulted impaired in HD,17 then we are currently investigating BDNF expression within the mouse colon. Although no significant changes in early-stage gut functionality (stool water content, body weight) were observed up to now, our findings suggest a neuroinflammatory response in the HD mouse colon, in line with what reported for other neurodegenerative diseases18 and reinforcing the importance of investigating peripheral symptoms in search for possible therapeutic strategies figure 1. References Aziz, N. A. et al. Weight loss in Huntington disease increases with higher CAG repeat number. Neurology 2008;71:1506–1513. Mochel F, et al. Early energy deficit in huntington disease: identification of a plasma biomarker traceable during disease progression. PLoS ONE 2007;2:e647. Roos RA. Huntington’s disease: a clinical review 2010;8. Aldaz T, et al. Non-motor symptoms in Huntington’s disease: a comparative study with Parkinson’s disease. J Neurol 2019;266:1340–1350. Fleming MA, Ehsan L, Moore SR, Levin DE. The enteric nervous system and its emerging role as a therapeutic target. Gastroenterol Res Pract 2020;2020:8024171. Furness JB, Callaghan BP, Rivera LR, Cho H-J. The enteric nervous system and gastrointestinal innervation: integrated local and central control. in Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease (eds. Lyte, M. & Cryan, J. F.) vol. 817 39–71 (Springer New York, New York, NY, 2014). Sharkey KA. Emerging roles for enteric glia in gastrointestinal disorders. J Clin Invest 2015;125:918–925. Scheperjans F, Derkinderen P, Borghammer P. The Gut and Parkinson’s Disease: Hype or Hope? J Parkinsons Dis 2018;8:S31–S39. Clairembault T, Leclair-Visonneau L, Neunlist M, Derkinderen P. Enteric glial cells: new players in Parkinson’s disease? Mov Disord 2015;30:494–498. Chen Q-Q, Haikal C, Li W, Li J-Y. Gut inflammation in association with pathogenesis of Parkinson’s disease. Front Mol Neurosci 2019;12:218. He X, et al. Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain. J Neuroinflammation 2021;18:153. van der Burg JMM, et al. Gastrointestinal dysfunction contributes to weight loss in Huntington’s disease mice. Neurobiology of Disease 2011;44:1–8. Moffitt H, McPhail GD, Woodman B, Hobbs C, Bates GP. Formation of polyglutamine inclusions in a wide range of non-CNS tissues in the HdhQ150 knock-in mouse model of Huntington’s disease. PLoS ONE 2009;4:e8025. Sathasivam K, et al. Formation of polyglutamine inclusions in non-CNS tissue. Human Molecular Genetics 1999;8:813–822. Menalled LB, Sison JD, Dragatsis I, Zeitlin S, Chesselet M-F. Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington’s disease with 140 CAG repeats. J. Comp. Neurol. 2003;465:11–26. Albini M, Krawczun-Rygmaczewska A, Cesca F. Astrocytes and brain-derived neurotrophic factor (BDNF). Neuroscience Research 2023;197:42–51. Zuccato C. Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington’s Disease. Science 2001;293:493–498. Devos D, et al. Colonic inflammation in Parkinson’s disease. Neurobiology of Disease 2013;50:42–48.

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