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

<h3></h3> While central nervous system symptoms in HD are well-documented, less attention has been given to peripheral symptoms like unintended weight-loss^{1 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. <h3>References</h3> Aziz, N. A. <i>et al.</i> Weight loss in Huntington disease increases with higher CAG repeat number. <i>Neurology</i> 2008;<b>71</b>:1506–1513. Mochel F, <i>et al.</i> Early energy deficit in huntington disease: identification of a plasma biomarker traceable during disease progression. <i>PLoS ONE</i> 2007;<b>2</b>:e647. Roos RA. Huntington’s disease: a clinical review 2010;<b>8</b>. Aldaz T, <i>et al.</i> Non-motor symptoms in Huntington’s disease: a comparative study with Parkinson’s disease. <i>J Neurol</i> 2019;<b>266</b>:1340–1350. Fleming MA, Ehsan L, Moore SR, Levin DE. The enteric nervous system and its emerging role as a therapeutic target. <i>Gastroenterol Res Pract</i> 2020;<b>2020</b>:8024171. Furness JB, Callaghan BP, Rivera LR, Cho H-J. The enteric nervous system and gastrointestinal innervation: integrated local and central control. in <i>Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease</i> (eds. Lyte, M. &amp; Cryan, J. F.) vol. <b>817</b> 39–71 (Springer New York, New York, NY, 2014). Sharkey KA. Emerging roles for enteric glia in gastrointestinal disorders. <i>J Clin Invest</i> 2015;<b>125</b>:918–925. Scheperjans F, Derkinderen P, Borghammer P. The Gut and Parkinson’s Disease: Hype or Hope? <i>J Parkinsons Dis</i> 2018;<b>8</b>:S31–S39. Clairembault T, Leclair-Visonneau L, Neunlist M, Derkinderen P. Enteric glial cells: new players in Parkinson’s disease? <i>Mov Disord</i> 2015;<b>30</b>:494–498. Chen Q-Q, Haikal C, Li W, Li J-Y. Gut inflammation in association with pathogenesis of Parkinson’s disease. <i>Front Mol Neurosci</i> 2019;<b>12</b>:218. He X, <i>et al.</i> Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain. <i>J Neuroinflammation</i> 2021;<b>18</b>:153. van der Burg JMM, <i>et al.</i> Gastrointestinal dysfunction contributes to weight loss in Huntington’s disease mice. <i>Neurobiology of Disease</i> 2011;<b>44</b>: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. <i>PLoS ONE</i> 2009;<b>4</b>:e8025. Sathasivam K, <i>et al.</i> Formation of polyglutamine inclusions in non-CNS tissue. <i>Human Molecular Genetics</i> 1999;<b>8</b>: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. <i>J. Comp. Neurol.</i> 2003;<b>465</b>:11–26. Albini M, Krawczun-Rygmaczewska A, Cesca F. Astrocytes and brain-derived neurotrophic factor (BDNF). <i>Neuroscience Research</i> 2023;<b>197</b>:42–51. Zuccato C. Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington’s Disease. <i>Science</i> 2001;<b>293</b>:493–498. Devos D, <i>et al.</i> Colonic inflammation in Parkinson’s disease. <i>Neurobiology of Disease</i> 2013;<b>50</b>:42–48.