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

Molecular Psychiatry volume 26, pages 5441–5463 (2021)Cite this article

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A Correction to this article was published on 24 July 2020

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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.

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Fig. 1: HTT/mHTT levels in blood and peripheral organs of parabionts.
Fig. 2: mHTT propagation and dilution in peripheral organs of parabionts.
Fig. 3: Mitochondrial function in peripheral organs of parabionts.
Fig. 4: Impact of parabiosis on striatal vasculature in parabionts.
Fig. 5: BBB disruption in parabionts.
Fig. 6: Impact of parabiosis on cortical HTT/mHTT levels of parabionts.
Fig. 7: Impact of parabiosis on neuronal and glial cell populations in parabionts.
Fig. 8: Summary of findings.

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Acknowledgements

FC is a recipient of a Researcher Chair from the Fonds de Recherche du Québec en Santé (FRQS) providing salary support and operating funds, and receives funding from the Canadian Institutes of Health Research (CIHR) to conduct her HD-related research. At this time of the study, MR and HLD were supported by a Desjardins scholarships from the Fondation du CHU de Québec, and later by doctoral training scholarships from the FRQS. GS is supported by a doctoral training scholarship from the FRQS and MA by a post-doctoral fellowship from the same funding agency. Sincere thanks to Dr. Gillian Bates for generously providing the S829 antibody.

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  1. These authors contributed equally: Marie Rieux, Melanie Alpaugh

Authors and Affiliations

  1. Centre de Recherche du CHU de Québec—Université Laval, Axe Neurosciences, 2705 boulevard Laurier, Québec, QC, G1V 4G2, Canada

    Marie Rieux, Melanie Alpaugh, Giacomo Sciacca, Martine Saint-Pierre, Maria Masnata, Hélèna L. Denis, Sébastien A. Lévesque, Abid Oueslati, Steve Lacroix & Francesca Cicchetti

  2. Département de Médecine Moléculaire, Université Laval, 1050 avenue de la Médecine, Québec, QC, G1V 0A6, Canada

    Marie Rieux, Sébastien A. Lévesque, Abid Oueslati & Steve Lacroix

  3. Département de Psychiatrie & Neurosciences, Université Laval, 1050 avenue de la Médecine, Québec, QC, G1V 0A6, Canada

    Melanie Alpaugh, Giacomo Sciacca, Maria Masnata, Hélèna L. Denis & Francesca Cicchetti

  4. Evotec SE, Essener Bogen 7, 22419, Hamburg, Germany

    Frank Herrmann & Chantal Bazenet

  5. L’Hôtel-Dieu de Québec—Université Laval, Axe Endocrinologie et Néphrologie, 10 rue McMahon, Québec, QC, G1R 2J6, Canada

    Alexandre P. Garneau & Paul Isenring

  6. Ecole de Kinésiologie et des Sciences de l’Activité Physique, Université de Montréal, 2100 boulevard Édouard-Montpetit, Montréal, QC, H3T 1J4, Canada

    Alexandre P. Garneau

  7. Department of Biochemistry and Biomedical Research, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada

    Ray Truant

  8. Département d’Anatomopathologie et de Cytologie, Centre Hospitalier Affilié Universitaire de Québec, Hôpital de l’Enfant-Jésus, 1401 18ème rue, Québec, QC, G1J 1Z4, Canada

    Peter V. Gould

  9. Neuroproteomics, Max Delbrueck Center for Molecular Medicine, 13125, Berlin, Germany

    Anne Ast & Erich E. Wanker

  10. Berlin Institute of Health, 10178, Berlin, Germany

    Anne Ast & Erich E. Wanker

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Rieux, M., Alpaugh, M., Sciacca, G. et al. Shedding a new light on Huntington’s disease: how blood can both propagate and ameliorate disease pathology. Mol Psychiatry 26, 5441–5463 (2021). https://doi.org/10.1038/s41380-020-0787-4

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