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Phenotypic diversity in ALS and the role of poly-conformational protein misfolding

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Abstract

In many types of familial amyotrophic lateral sclerosis (fALS), mutations cause proteins to gain toxic properties that mediate neurodegenerative processes. It is becoming increasingly clear that the proteins involved in ALS, and those responsible for a host of other neurodegenerative diseases, share many characteristics with a growing number of prion diseases. ALS is a heterogenous disease in which the majority of cases are sporadic in their etiology. Studies investigating the inherited forms of the disease are now beginning to provide evidence that some of this heterogeneity may be due to the existence of distinct conformations that ALS-linked proteins can adopt to produce the equivalent of prion strains. In this review, we discuss the in vitro and in vivo evidence that has been generated to better understand the characteristics of these proteins and how their tertiary structure may impact the disease phenotype.

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Acknowledgements

This work was supported by a grant from the National Institutes of Neurological Disease and Stroke (1R01NA092788-01).

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  1. Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, 94143, USA

    Jacob I. Ayers

  2. Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, 32610, USA

    David R. Borchelt

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Ayers, J.I., Borchelt, D.R. Phenotypic diversity in ALS and the role of poly-conformational protein misfolding. Acta Neuropathol 142, 41–55 (2021). https://doi.org/10.1007/s00401-020-02222-x

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