Combating neurodegenerative disease with chemical probes and model systems

A Corrigendum to this article was published on 20 January 2015

This article has been updated

Abstract

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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Figure 1: Balancing act of proteostasis and potential perturbations driving disease.
Figure 2: Small molecules targeting the processing of APP.
Figure 3: Comparison of select eukaryotic model systems for their potential for chemical biological approaches and drug discovery in NDs.
Figure 4: Tafamidis targets TTR to stabilize folded, functional tetramers.

Change history

  • 11 December 2014

    In the version of this paper originally published, the 'phase' entry for PBT2 in Table 1 was inadvertently labeled as 'Discontinued'. It has now been corrected to phase 2. Additionally, at the time of this corrigendum, the U.S. Food and Drug Administration status of AZD3293 has changed to phase 2/3 on Alzforum's database of amyloid-related therapeutics, and Epothilone D has been discontinued. Lastly, BIIB037 (Aducanumab) has been announced to be proceeding to phase 3 trials. The respective table entries have been amended to reflect these changes in the HTML and PDF versions of the article.

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Acknowledgements

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.

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Correspondence to Susan Lindquist.

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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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