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Current and future applications of induced pluripotent stem cell-based models to study pathological proteins in neurodegenerative disorders

Molecular Psychiatry volume 26, pages 2685–2706 (2021)Cite this article

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A Correction to this article was published on 09 March 2021

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Abstract

Neurodegenerative disorders emerge from the failure of intricate cellular mechanisms, which ultimately lead to the loss of vulnerable neuronal populations. Research conducted across several laboratories has now provided compelling evidence that pathogenic proteins can also contribute to non-cell autonomous toxicity in several neurodegenerative contexts, including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as Amyotrophic Lateral Sclerosis. Given the nearly ubiquitous nature of abnormal protein accumulation in such disorders, elucidating the mechanisms and routes underlying these processes is essential to the development of effective treatments. To this end, physiologically relevant human in vitro models are critical to understand the processes surrounding uptake, release and nucleation under physiological or pathological conditions. This review explores the use of human-induced pluripotent stem cells (iPSCs) to study prion-like protein propagation in neurodegenerative diseases, discusses advantages and limitations of this model, and presents emerging technologies that, combined with the use of iPSC-based models, will provide powerful model systems to propel fundamental research forward.

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Fig. 1: Prion-like proteins in human diseases and iPSC models.
Fig. 2: Challenges and perspectives of iPSCs for modeling proteinopathies.

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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. MA is supported by post-doctoral fellowships from both CIHR and FRQS and 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

    Aurélie de Rus Jacquet, Hélèna L. Denis, Francesca Cicchetti & Melanie Alpaugh

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

    Aurélie de Rus Jacquet, Hélèna L. Denis, Francesca Cicchetti & Melanie Alpaugh

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ARJ and MA researched data for the article and wrote the manuscript. HLD designed the figures and tables. FC contributed to discussions and helped edit the manuscript. All authors reviewed the content before publication.

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Correspondence to Francesca Cicchetti or Melanie Alpaugh.

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de Rus Jacquet, A., Denis, H.L., Cicchetti, F. et al. Current and future applications of induced pluripotent stem cell-based models to study pathological proteins in neurodegenerative disorders. Mol Psychiatry 26, 2685–2706 (2021). https://doi.org/10.1038/s41380-020-00999-7

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