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Decoding ALS: from genes to mechanism

Author

Listed:
  • J. Paul Taylor

    (St. Jude Children's Research Hospital)

  • Robert H. Brown

    (University of Massachusetts Medical School)

  • Don W. Cleveland

    (Ludwig Institute for Cancer Research, University of California
    University of California)

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.

Suggested Citation

  • J. Paul Taylor & Robert H. Brown & Don W. Cleveland, 2016. "Decoding ALS: from genes to mechanism," Nature, Nature, vol. 539(7628), pages 197-206, November.
    • Handle: RePEc:nat:nature:v:539:y:2016:i:7628:d:10.1038_nature20413
    DOI: 10.1038/nature20413
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    1. Topaz Altman & Ariel Ionescu & Amjad Ibraheem & Dominik Priesmann & Tal Gradus-Pery & Luba Farberov & Gayster Alexandra & Natalia Shelestovich & Ruxandra Dafinca & Noam Shomron & Florence Rage & Kevin, 2021. "Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. Jaime Carrasco & Rosa Antón & Alejandro Valbuena & David Pantoja-Uceda & Mayur Mukhi & Rubén Hervás & Douglas V. Laurents & María Gasset & Javier Oroz, 2023. "Metamorphism in TDP-43 prion-like domain determines chaperone recognition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Laura Matabishi-Bibi & Drice Challal & Mara Barucco & Domenico Libri & Anna Babour, 2022. "Termination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Jessica Mandrioli & Roberto D’Amico & Elisabetta Zucchi & Sara De Biasi & Federico Banchelli & Ilaria Martinelli & Cecilia Simonini & Domenico Lo Tartaro & Roberto Vicini & Nicola Fini & Giulia Gianfe, 2023. "Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Federica Raguseo & Yiran Wang & Jessica Li & Marija Petrić Howe & Rubika Balendra & Anouk Huyghebaert & Devkee M. Vadukul & Diana A. Tanase & Thomas E. Maher & Layla Malouf & Roger Rubio-Sánchez & Fra, 2023. "The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Jie Zhong & Chaodong Wang & Dan Zhang & Xiaoli Yao & Quanzhen Zhao & Xusheng Huang & Feng Lin & Chun Xue & Yaqing Wang & Ruojie He & Xu-Ying Li & Qibin Li & Mingbang Wang & Shaoli Zhao & Shabbir Khan , 2024. "PCDHA9 as a candidate gene for amyotrophic lateral sclerosis," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    7. Yoshifumi Sonobe & Jihad Aburas & Gopinath Krishnan & Andrew C. Fleming & Ghanashyam Ghadge & Priota Islam & Eleanor C. Warren & Yuanzheng Gu & Mark W. Kankel & André E. X. Brown & Evangelos Kiskinis , 2021. "A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    8. Hye Ji Cha & Özgün Uyan & Yan Kai & Tianxin Liu & Qian Zhu & Zuzana Tothova & Giovanni A. Botten & Jian Xu & Guo-Cheng Yuan & Job Dekker & Stuart H. Orkin, 2021. "Inner nuclear protein Matrin-3 coordinates cell differentiation by stabilizing chromatin architecture," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    9. Sheng Chen & Anuradhika Puri & Braxton Bell & Joseph Fritsche & Hector H. Palacios & Maurie Balch & Macy L. Sprunger & Matthew K. Howard & Jeremy J. Ryan & Jessica N. Haines & Gary J. Patti & Albert A, 2024. "HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    10. Renata Vieira de Sá & Emma Sudria-Lopez & Marta Cañizares Luna & Oliver Harschnitz & Dianne M. A. Heuvel & Sandra Kling & Danielle Vonk & Henk-Jan Westeneng & Henk Karst & Lauri Bloemenkamp & Suzy Var, 2024. "ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    11. Malgorzata J. Latallo & Shaopeng Wang & Daoyuan Dong & Blake Nelson & Nathan M. Livingston & Rong Wu & Ning Zhao & Timothy J. Stasevich & Michael C. Bassik & Shuying Sun & Bin Wu, 2023. "Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    12. Lynne Cassimeris & Jessica C Leung & David J Odde, 2018. "Monte Carlo simulations of microtubule arrays: The critical roles of rescue transitions, the cell boundary, and tubulin concentration in shaping microtubule distributions," PLOS ONE, Public Library of Science, vol. 13(5), pages 1-20, May.
    13. Ji Geng & Shuangxi Li & Yu Li & Zhihao Wu & Sunil Bhurtel & Suman Rimal & Danish Khan & Rani Ohja & Onn Brandman & Bingwei Lu, 2024. "Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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