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

Nature | Mar 28, 2013

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.

Pubmed ID: 23455423 RIS Download

Mesh terms: Amino Acid Sequence | Amyotrophic Lateral Sclerosis | Animals | Drosophila melanogaster | Female | Frontotemporal Dementia | HeLa Cells | Heterogeneous-Nuclear Ribonucleoprotein Group A-B | Humans | Inclusion Bodies | Male | Mice | Molecular Sequence Data | Muscular Dystrophies, Limb-Girdle | Mutant Proteins | Mutation | Myositis, Inclusion Body | Osteitis Deformans | Peptide Termination Factors | Prions | Protein Structure, Tertiary | RNA | Saccharomyces cerevisiae Proteins

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Associated grants

  • Agency: NIA NIH HHS, Id: P01 AG032953
  • Agency: NINDS NIH HHS, Id: NS053825
  • Agency: Wellcome Trust, Id: 089701
  • Agency: Medical Research Council, Id: MC_G1000733
  • Agency: NIA NIH HHS, Id: K02 AG042095
  • Agency: NINDS NIH HHS, Id: R01 NS053825
  • Agency: NIA NIH HHS, Id: AG031867
  • Agency: Medical Research Council, Id: G0900688
  • Agency: NIH HHS, Id: DP2 OD002177
  • Agency: NIA NIH HHS, Id: AG032953
  • Agency: NIH HHS, Id: DP2OD002177
  • Agency: NINDS NIH HHS, Id: R21 NS067354
  • Agency: NIA NIH HHS, Id: R01 AG031867
  • Agency: NINDS NIH HHS, Id: NS067354

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