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

Neurobiology of Disease

Giulia Cisbani¹  Erwan Bezard²  Alexander Maxan³  Abid Oueslati³  Francesca Cicchetti³  Jean-Paul G. Vonsattel³  Philippe Gosset³  Melanie Alpaugh³  Zhu Tao⁴  Zhang Ling⁴  Chuan Qin⁴  Steve Lacroix⁵  Nadia Fortin⁶  Benjamin Dehay⁷  Ludivine Breger⁷ 

[1] Correspondence to: C Qin, Institute of Laboratory Animal Science, Chinese Academy of Medical Science, 5 Panjiayuan Nanli Chaoyang District, Beijing 100021, China.;Département de Médicine Moléculaire, Université Laval, Québec, QC G1K 0A6, Canada;Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC G1V 4G2, Canada;Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China;New-York Brain Bank, Columbia University, New York, NY 10032, United States;University of Toronto, Department of Nutritional Sciences, Toronto, ON M5S 1A8, Canada;Université de Bordeaux, Institut des maladies neurodégénératives, UMR 5293, Bordeaux CNRS UMR 5293, France;

关键词: Animal behaviour;    BACHD;    Huntingtin;    Huntington's disease;    Neurodegenerative diseases;    Pathological polyQ;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown