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

被引:0
作者
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
J. Paul Taylor
机构
[1] St Jude Children’s Research Hospital,Department of Developmental Neurobiology
[2] Hartwell Center for Bioinformatics and Biotechnology,Department of Biochemistry and Biophysics
[3] St Jude Children’s Research Hospital,Department of Biochemistry and Molecular Biology
[4] Perelman School of Medicine at the University of Pennsylvania,Department of Computational Biology
[5] Colorado State University,Department of Neuroscience
[6] St Jude Children’s Research Hospital,Department of Neurology
[7] Mayo Clinic,Department of Pathology and Laboratory Medicine
[8] Brigham and Women’s Hospital,Department of Clinical Neuroscience
[9] Harvard Medical School,Division of Neuropediatrics and Muscle Disorders
[10] Institute on Aging and Center for Neurodegenerative Disease Research,Department of Neurology
[11] Perelman School of Medicine at the University of Pennsylvania,Department of Genetics
[12] Neuromuscular Diseases Research Group,Neurology Department
[13] Laboratory of Neurogenetics,Department of Pediatrics, Division of Genetics and Metabolism
[14] Porter Neuroscience Building,undefined
[15] National Institute on Aging,undefined
[16] National Institutes of Health,undefined
[17] King’s College London Centre for Neurodegeneration Research,undefined
[18] Institute of Psychiatry,undefined
[19] London SE5 8AF,undefined
[20] UK,undefined
[21] University Children’s Hospital Freiburg,undefined
[22] 79106 Freiburg,undefined
[23] Germany,undefined
[24] Washington University School of Medicine,undefined
[25] Medical Scientist Training Program,undefined
[26] Perelman School of Medicine at the University of Pennsylvania,undefined
[27] Stanford University School of Medicine,undefined
[28] University of Miami Miller School of Medicine,undefined
[29] Boston Biomedical Research Institute,undefined
[30] University of California-Irvine,undefined
[31] 2501 Hewitt Hall,undefined
[32] Irvine,undefined
[33] California 92696,undefined
[34] USA,undefined
来源
Nature | 2013年 / 495卷
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摘要
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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页码:467 / 473
页数:6
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