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Evidence for the spread of human-derived mutant huntingtin protein in mice and non-human primates

Abstract : In recent years, substantial evidence has emerged to suggest that spreading of pathological proteins contributes to disease pathology in numerous neurodegenerative disorders. Work from our laboratory and others have shown that, despite its strictly genetic nature, Huntington's disease (HD) may be another condition in which this mechanism contributes to pathology. In this study, we set out to determine if the mutant huntingtin protein (mHTT) present in post-mortem brain tissue derived from HD patients can induce pathology in mice and/or non-human primates. For this, we performed three distinct sets of experiments where homogenates were injected into the brains of adult a) Wild-type (WT) and b) BACHD mice or c) non-human primates. Neuropathological assessments revealed that, while changes in the endogenous huntingtin were not apparent, mHTT could spread between cellular elements and brain structures. Furthermore, behavioural differences only occurred in the animal model of HD which already overexpressed mHTT. Taken together, our results indicate that mHTT derived from human brains has only a limited capacity to propagate between cells and does not depict prion-like characteristics. This contrasts with recent work demonstrating that other forms of mHTT - such as fibrils of a pathological polyQ length or fibroblasts and induced pluripotent stem cells derived from HD cases - can indeed disseminate disease throughout the brain in a prion-like fashion.
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Contributor : Benjamin Dehay Connect in order to contact the contributor
Submitted on : Wednesday, May 20, 2020 - 10:55:13 AM
Last modification on : Tuesday, May 3, 2022 - 3:14:04 PM

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Philippe Gosset, Alexander Maxan, Melanie Alpaugh, Ludivine Breger, Benjamin Dehay, et al.. Evidence for the spread of human-derived mutant huntingtin protein in mice and non-human primates. Neurobiology of Disease, Elsevier, 2020, 141, pp.104941. ⟨10.1016/j.nbd.2020.104941⟩. ⟨inserm-02613508⟩



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