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

Autor: Gosset P; Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC G1V 4G2, Canada., Maxan A; Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC G1V 4G2, Canada., Alpaugh M; Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC G1V 4G2, Canada., Breger L; Université de Bordeaux, Institut des maladies neurodégénératives, UMR 5293, Bordeaux CNRS UMR 5293, France., Dehay B; Université de Bordeaux, Institut des maladies neurodégénératives, UMR 5293, Bordeaux CNRS UMR 5293, France., Tao Z; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China., Ling Z; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China., Qin C; Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China. Electronic address: qinchuan@pumc.edu.cn., Cisbani G; University of Toronto, Department of Nutritional Sciences, Toronto, ON M5S 1A8, Canada., Fortin N; Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC G1V 4G2, Canada., Vonsattel JG; New-York Brain Bank, Columbia University, New York, NY 10032, United States., Lacroix S; Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC G1V 4G2, Canada; Département de Médicine Moléculaire, Université Laval, Québec, QC G1K 0A6, Canada., Oueslati A; Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC G1V 4G2, Canada; Département de Médicine Moléculaire, Université Laval, Québec, QC G1K 0A6, Canada., Bezard E; Université de Bordeaux, Institut des maladies neurodégénératives, UMR 5293, Bordeaux CNRS UMR 5293, France., Cicchetti F; Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC G1V 4G2, Canada; Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC G1K 0A6, Canada. Electronic address: francesca.cicchetti@crchudequebec.ulaval.ca.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2020 Jul; Vol. 141, pp. 104941. Date of Electronic Publication: 2020 May 11.
DOI: 10.1016/j.nbd.2020.104941
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare no competing interest.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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