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

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 Carter, Kevin B. Boylan, Aleksandra M. Wojtas, Rosa Rademakers, Jack L. Pinkus, Steven A. Greenberg, John Q. Trojanowski, Bryan J. Traynor, Bradley N. Smith, Simon Topp, Athina-Soragia Gkazi, Jack Miller, Christopher E. Shaw, Michael Kottlors, Janbernd Kirschner, Alan Pestronk, Yun R. Li, Alice Flynn Ford, Aaron D. Gitler, Michael Benatar, Oliver D. King, Virginia E. Kimonis, Eric D. Ross, Conrad C. Weihl, James Shorter () and J. Paul Taylor ()
Additional contact information
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

Nature, 2013, vol. 495, issue 7442, 467-473

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature11922

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