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Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS

Author

Listed:
  • Hong Joo Kim

    (St Jude Children’s Research Hospital)

  • Nam Chul Kim

    (St Jude Children’s Research Hospital)

  • Yong-Dong Wang

    (Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital)

  • Emily A. Scarborough

    (Perelman School of Medicine at the University of Pennsylvania)

  • Jennifer Moore

    (St Jude Children’s Research Hospital)

  • Zamia Diaz

    (Perelman School of Medicine at the University of Pennsylvania)

  • Kyle S. MacLea

    (Colorado State University)

  • Brian Freibaum

    (St Jude Children’s Research Hospital)

  • Songqing Li

    (St Jude Children’s Research Hospital)

  • Amandine Molliex

    (St Jude Children’s Research Hospital)

  • Anderson P. Kanagaraj

    (St Jude Children’s Research Hospital)

  • Robert Carter

    (St Jude Children’s Research Hospital)

  • Kevin B. Boylan

    (Mayo Clinic)

  • Aleksandra M. Wojtas

    (Mayo Clinic)

  • Rosa Rademakers

    (Mayo Clinic)

  • Jack L. Pinkus

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Steven A. Greenberg

    (Brigham and Women’s Hospital, Harvard Medical School)

  • John Q. Trojanowski

    (Institute on Aging and Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania)

  • Bryan J. Traynor

    (Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, Porter Neuroscience Building, National Institute on Aging, National Institutes of Health)

  • Bradley N. Smith

    (Institute on Aging and Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania)

  • Simon Topp

    (King’s College London Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK)

  • Athina-Soragia Gkazi

    (King’s College London Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK)

  • Jack Miller

    (King’s College London Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK)

  • Christopher E. Shaw

    (King’s College London Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK)

  • Michael Kottlors

    (University Children’s Hospital Freiburg, 79106 Freiburg, Germany)

  • Janbernd Kirschner

    (University Children’s Hospital Freiburg, 79106 Freiburg, Germany)

  • Alan Pestronk

    (Washington University School of Medicine)

  • Yun R. Li

    (Medical Scientist Training Program, Perelman School of Medicine at the University of Pennsylvania)

  • Alice Flynn Ford

    (Perelman School of Medicine at the University of Pennsylvania)

  • Aaron D. Gitler

    (Stanford University School of Medicine)

  • Michael Benatar

    (University of Miami Miller School of Medicine)

  • Oliver D. King

    (Boston Biomedical Research Institute)

  • Virginia E. Kimonis

    (University of California-Irvine, 2501 Hewitt Hall, Irvine, California 92696, USA)

  • Eric D. Ross

    (Colorado State University)

  • Conrad C. Weihl

    (Washington University School of Medicine)

  • James Shorter

    (Perelman School of Medicine at the University of Pennsylvania)

  • J. Paul Taylor

    (St Jude Children’s Research Hospital)

Abstract

Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

Suggested Citation

  • Hong Joo Kim & Nam Chul Kim & Yong-Dong Wang & Emily A. Scarborough & Jennifer Moore & Zamia Diaz & Kyle S. MacLea & Brian Freibaum & Songqing Li & Amandine Molliex & Anderson P. Kanagaraj & Robert Ca, 2013. "Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS," Nature, Nature, vol. 495(7442), pages 467-473, March.
  • Handle: RePEc:nat:nature:v:495:y:2013:i:7442:d:10.1038_nature11922
    DOI: 10.1038/nature11922
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    Cited by:

    1. Tao Wang & Xibin Tian & Han Byeol Kim & Yura Jang & Zhiyuan Huang & Chan Hyun Na & Jiou Wang, 2022. "Intracellular energy controls dynamics of stress-induced ribonucleoprotein granules," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    2. Hannah E. Salapa & Patricia A. Thibault & Cole D. Libner & Yulian Ding & Joseph-Patrick W. E. Clarke & Connor Denomy & Catherine Hutchinson & Hashim M. Abidullah & S. Austin Hammond & Landon Pastushok, 2024. "hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Amir Pozner & Li Li & Shiv Prakash Verma & Shuxin Wang & Jared J. Barrott & Mary L. Nelson & Jamie S. E. Yu & Gian Luca Negri & Shane Colborne & Christopher S. Hughes & Ju-Fen Zhu & Sydney L. Lambert , 2024. "ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    4. Javier Garcia-Pardo & Andrea Bartolomé-Nafría & Antonio Chaves-Sanjuan & Marcos Gil-Garcia & Cristina Visentin & Martino Bolognesi & Stefano Ricagno & Salvador Ventura, 2023. "Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Keren Lasker & Steven Boeynaems & Vinson Lam & Daniel Scholl & Emma Stainton & Adam Briner & Maarten Jacquemyn & Dirk Daelemans & Ashok Deniz & Elizabeth Villa & Alex S. Holehouse & Aaron D. Gitler & , 2022. "The material properties of a bacterial-derived biomolecular condensate tune biological function in natural and synthetic systems," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Hong Joo Kim & Payam Mohassel & Sandra Donkervoort & Lin Guo & Kevin O’Donovan & Maura Coughlin & Xaviere Lornage & Nicola Foulds & Simon R. Hammans & A. Reghan Foley & Charlotte M. Fare & Alice F. Fo, 2022. "Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. Raju Roy & Gitartha Das & Ishwarya Achappa Kuttanda & Nupur Bhatter & Purusharth I. Rajyaguru, 2022. "Low complexity RGG-motif sequence is required for Processing body (P-body) disassembly," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    8. Andrea Wilderman & Eva D’haene & Machteld Baetens & Tara N. Yankee & Emma Wentworth Winchester & Nicole Glidden & Ellen Roets & Jo Dorpe & Sandra Janssens & Danny E. Miller & Miranda Galey & Kari M. B, 2024. "A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    9. Mina Farag & Wade M. Borcherds & Anne Bremer & Tanja Mittag & Rohit V. Pappu, 2023. "Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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