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.

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Acknowledgements

We thank the patients whose participation made this work possible. We thank the St Jude Pediatric Cancer Genome Project and J. Zhang in particular for providing access to control sequencing data. We thank C. Gellera, B. Baloh, M. Harms, S. Krause, G. Dreyfuss and T. Cundy for sharing reagents. We thank S. Donkervoort and S. Mumm for coordinating samples, and A. Taylor for editorial assistance. J.P.T. was supported by ALSAC, the Packard Foundation and the National Institutes of Health (NIH) (NS053825); J.P.T. and M.B. were supported by the ALS Association; J.Q.T. was supported by the NIH (AG032953); J.S. was supported by the NIH (DP2OD002177 and NS067354) and the Ellison Medical Foundation; E.D.R. was supported by the National Science Foundation (MCB-1023771). C.C.W. was supported by the NIH (AG031867).

Author information

Author notes

    • Hong Joo Kim
    • , Nam Chul Kim
    • , Yong-Dong Wang
    • , Emily A. Scarborough
    • , Jennifer Moore
    •  & Zamia Diaz

    These authors contributed equally to this work.

Affiliations

  1. Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, Tennessee 38120, USA

    • Hong Joo Kim
    • , Nam Chul Kim
    • , Jennifer Moore
    • , Brian Freibaum
    • , Songqing Li
    • , Amandine Molliex
    • , Anderson P. Kanagaraj
    •  & J. Paul Taylor
  2. Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital, Memphis, Tennessee 38120, USA

    • Yong-Dong Wang
  3. Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Emily A. Scarborough
    • , Zamia Diaz
    • , Alice Flynn Ford
    •  & James Shorter
  4. Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523, USA

    • Kyle S. MacLea
    •  & Eric D. Ross
  5. Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, Tennessee 38120, USA

    • Robert Carter
  6. Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA

    • Kevin B. Boylan
    • , Aleksandra M. Wojtas
    •  & Rosa Rademakers
  7. Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Jack L. Pinkus
    •  & Steven A. Greenberg
  8. Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • John Q. Trojanowski
    •  & Bradley N. Smith
  9. Neuromuscular Diseases Research Group, Laboratory of Neurogenetics, Porter Neuroscience Building, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Bryan J. Traynor
  10. King’s College London Centre for Neurodegeneration Research, Department of Clinical Neuroscience, Institute of Psychiatry, London SE5 8AF, UK

    • Simon Topp
    • , Athina-Soragia Gkazi
    • , Jack Miller
    •  & Christopher E. Shaw
  11. Division of Neuropediatrics and Muscle Disorders, University Children’s Hospital Freiburg, 79106 Freiburg, Germany

    • Michael Kottlors
    •  & Janbernd Kirschner
  12. Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA

    • Alan Pestronk
    •  & Conrad C. Weihl
  13. Medical Scientist Training Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Yun R. Li
  14. Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA

    • Aaron D. Gitler
  15. Neurology Department, University of Miami Miller School of Medicine, Miami, Florida 33136, USA

    • Michael Benatar
  16. Boston Biomedical Research Institute, Watertown, Massachusetts 02472, USA

    • Oliver D. King
  17. Department of Pediatrics, Division of Genetics and Metabolism, University of California-Irvine, 2501 Hewitt Hall, Irvine, California 92696, USA

    • Virginia E. Kimonis

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Contributions

H.J.K., N.C.K., E.D.R., C.C.W., J.S. and J.P.T. designed experiments. H.J.K., N.C.K., E.A.S., J.Moore, Z.D., K.S.M., B.F., S.L., A.M., A.P.K., Y.R.L. and A.F.F. performed the experiments. K.B.B., A.M.W., R.R., J.L.P., S.A.G., J.Q.T., B.N.S., S.T., A.-S.G., J.Miller, C.E.S., M.K., J.K., A.P., M.B. and V.E.K. provided patient clinical material, clinical evaluation, or evaluation of patient clinical material. H.J.K., N.C.K., Y.-D.W., R.C., B.J.T., A.D.G., O.D.K., E.D.R., J.S. and J.P.T. contributed to data analysis. E.D.R., O.D.K. and C.C.W. contributed to manuscript preparation. H.J.K., J.S. and J.P.T. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to James Shorter or J. Paul Taylor.

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    Supplementary Information

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DOI

https://doi.org/10.1038/nature11922

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