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Shedding a new light on Huntington's disease: how blood can both propagate and ameliorate disease pathology

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Item Type:Article
Title:Shedding a new light on Huntington's disease: how blood can both propagate and ameliorate disease pathology
Creators Name:Rieux, M. and Alpaugh, M. and Sciacca, G. and Saint-Pierre, M. and Masnata, M. and Denis, H.L. and Lévesque, S.A. and Herrmann, F. and Bazenet, C. and Garneau, A.P. and Isenring, P. and Truant, R. and Oueslati, A. and Gould, P.V. and Ast, A. and Wanker, E.E. and Lacroix, S. and Cicchetti, F.
Abstract:Huntington's disease (HD) is a monogenic neurodegenerative disorder resulting from a mutation in the huntingtin gene. This leads to the expression of the mutant huntingtin protein (mHTT) which provokes pathological changes in both the central nervous system (CNS) and periphery. Accumulating evidence suggests that mHTT can spread between cells of the CNS but here, we explored the possibility that mHTT could also propagate and cause pathology via the bloodstream. For this, we used a parabiosis approach to join the circulatory systems of wild-type (WT) and zQ175 mice. After surgery, we observed mHTT in the plasma and circulating blood cells of WT mice and post-mortem analyses revealed the presence of mHTT aggregates in several organs including the liver, kidney, muscle and brain. The presence of mHTT in the brain was accompanied by vascular abnormalities, such as a reduction of Collagen IV signal intensity and altered vessel diameter in the striatum, and changes in expression of Glutamic acid decarboxylase 65/67 (GAD65-67) in the cortex. Conversely, we measured reduced pathology in zQ175 mice by decreased mitochondrial impairments in peripheral organs, restored vessel diameter in the cortex and improved expression of Dopamine- and cAMP-regulated phosphoprotein 32 (DARPP32) in striatal neurons. Collectively, these results demonstrate that circulating mHTT can disseminate disease, but importantly, that healthy blood can dilute pathology. These findings have significant implications for the development of therapies in HD.
Keywords:Animal Disease Models, Corpus Striatum, Dopamine and cAMP-Regulated Phosphoprotein 32, Huntingtin Protein, Huntington Disease, Neurons, Transgenic Mice, Animals, Mice
Source:Molecular Psychiatry
Publisher:Nature Publishing Group
Page Range:5441–5463
Date:September 2020
Additional Information:Erratum in: Mol Psychiatry 24 Jul 2020 [in Press].
Official Publication:https://doi.org/10.1038/s41380-020-0787-4
PubMed:View item in PubMed

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