The disheartening results of recent clinical trials for neurodegenerative disease (ND) therapeutics underscore the need for a more comprehensive understanding of the underlying disease biology before effective therapies can be devised. One hallmark of many NDs is a disruption in protein homeostasis. Therefore, investigating the role of protein homeostasis in these diseases is central to delineating their underlying pathobiology. Here, we review the seminal role that chemical biology has played in furthering the research on and treatment of dysfunctional protein homeostasis in NDs. We also discuss the vital and predictive role of model systems in identifying conserved homeostasis pathways and genes therein that are altered in neurodegeneration. Integrating approaches from chemical biology with the use of model systems yields a powerful toolkit with which to unravel the complexities of ND biology.
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We apologize to colleagues whose work could not be cited owing to space limitations. We would like to thank L.K. Clayton and members of the Lindquist laboratory; K. Rhodes, N.M. Bonini and G.A. Caldwell for critical reading of the manuscript; and Thomas DiCesare for assistance with the figures. S.L. is an investigator with the Howard Hughes Medical Institute. P.N. is supported by the JPB Foundation and the Helen Hay Whitney Foundation. S.E. is supported by the Canadian Institutes of Health Research.
The authors declare no competing financial interests.
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Narayan, P., Ehsani, S. & Lindquist, S. Combating neurodegenerative disease with chemical probes and model systems. Nat Chem Biol 10, 911–920 (2014). https://doi.org/10.1038/nchembio.1663
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