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Prion-like properties of the mutant huntingtin protein in living organisms: the evidence and the relevance

Molecular Psychiatry volume 27, pages 269–280 (2022)Cite this article

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Abstract

If theories postulating that pathological proteins associated with neurodegenerative disorders behave similarly to prions were initially viewed with reluctance, it is now well-accepted that this occurs in several disease contexts. Notably, it has been reported that protein misfolding and subsequent prion-like properties can actively participate in neurodegenerative disorders. While this has been demonstrated in multiple cellular and animal model systems related to Alzheimer’s and Parkinson’s diseases, the prion-like properties of the mutant huntingtin protein (mHTT), associated with Huntington’s disease (HD), have only recently been considered to play a role in this pathology, a concept our research group has contributed to extensively. In this review, we summarize the last few years of in vivo research in the field and speculate on the relationship between prion-like events and human HD. By interpreting observations primarily collected in in vivo models, our discussion will aim to discriminate which experimental factors contribute to the most efficient types of prion-like activities of mHTT and which routes of propagation may be more relevant to the human condition. A look back at nearly a decade of experimentation will inform future research and whether therapeutic strategies may emerge from this new knowledge.

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Fig. 1: Routes of mHTT spread.
Fig. 2: Efficiency of mHTT spreading and seeding: key factors.
Fig. 3: The relevance of prion-like mHTT properties to clinical HD.

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Acknowledgements

FC is a recipient of a Researcher Chair from the Fonds de Recherche du Québec en Santé (FRQS) (grant # 28941) providing salary support and operating funds and receives funding from the Canadian Institutes of Health Research (CIHR) to conduct her HD-related research (Grant # PJT-168865 and PJT-162164). MA was supported by post-doctoral fellowships from CIHR, FRQS and the Huntington Disease Society of America (HDSA) during the course of the work described herein. HLD is supported by an FRQS doctoral research award.

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  1. Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences, Québec, QC, G1V 4G2, Canada

    Melanie Alpaugh, Hélèna L. Denis & Francesca Cicchetti

  2. Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada

    Melanie Alpaugh, Hélèna L. Denis & Francesca Cicchetti

Authors
  1. Melanie Alpaugh
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  2. Hélèna L. Denis
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  3. Francesca Cicchetti
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Contributions

MA conceptualization; roles/writing—original draft; writing—review and editing. HLD conceptualization; visualization; writing—review and editing. FC conceptualization; writing—review and editing; supervision.

Corresponding author

Correspondence to Francesca Cicchetti.

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Alpaugh, M., Denis, H.L. & Cicchetti, F. Prion-like properties of the mutant huntingtin protein in living organisms: the evidence and the relevance. Mol Psychiatry 27, 269–280 (2022). https://doi.org/10.1038/s41380-021-01350-4

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  • DOI: https://doi.org/10.1038/s41380-021-01350-4

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