2. Academic Validation
  3. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS

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

  • Nature. 2013 Mar 28;495(7442):467-73. doi: 10.1038/nature11922.
Hong Joo Kim 1,  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
Affiliations

Affiliation

  • 1 Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38120, USA.
PMID: 23455423 DOI: 10.1038/nature11922
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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