Review Article | Published:

Decoding ALS: from genes to mechanism

Nature volume 539, pages 197206 (10 November 2016) | Download Citation

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors have been identified that drive the degeneration of motor neurons in ALS, increase susceptibility to the disease or influence the rate of its progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, the induction of stress at the endoplasmic reticulum and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through liquid–liquid phase separation. Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified.

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Acknowledgements

We apologize for the many studies we were unable to cite because of space limitations. The authors gratefully acknowledge the artwork and editorial assistance provided by N. Nedelsky and H.-J. Kim and the provision of histopathology images by J. Ravits and S. Saberi. J.P.T. receives support from the Howard Hughes Medical Institute, the US National Institute of Neurological Disorders and Stroke (NINDS), the American Lebanese Syrian Associated Charities, Target ALS and the US ALS Association. R.H.B. receives support from NINDS, the ALS Association, ALS Finding a Cure, ALS ONE, the Angel Fund for ALS Research and Project ALS. D.W.C. receives salary support from the Ludwig Institute for Cancer Research and is supported by funding from NINDS (R01 NS27036), the ALS Association and Target ALS.

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  1. Howard Hughes Medical Institute and the Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

    • J. Paul Taylor
  2. Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.

    • Robert H. Brown Jr
  3. Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California 92093, USA.

    • Don W. Cleveland
  4. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA.

    • Don W. Cleveland

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Competing interests

J.P.T. is a consultant for Inception Biosciences. D.W.C. is a consultant for Ionis Pharmaceuticals.

Corresponding authors

Correspondence to J. Paul Taylor or Robert H. Brown Jr or Don W. Cleveland.

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Reviewer Information Nature thanks I. Dikic, J. Rothstein and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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