Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS
Wellstone Center for FSHD
Medical Subject Headings
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
Cell Biology | Developmental Biology | Molecular Biology | Molecular Genetics | Musculoskeletal Diseases | Nervous System Diseases
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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Citation: Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP. 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. Link to article on publisher's site
Kim, Hong Joo; Kim, Nam Chul; Wang, Yong-Dong; Scarborough, Emily A.; Moore, Jennifer; Diaz, Zamia; MacLea, Kyle S.; Freibaum, Brian; Li, Songqing; Molliex, Amandine; Kanagaraj, Anderson P.; Carter, Robert; Boylan, Kevin B.; Wojtas, Aleksandra M.; Rademakers, Rosa; Pinkus, Jack L.; Greenberg, Steven A.; Trojanowski, John Q.; Traynor, Bryan J.; Smith, Bradley N.; Topp, Simon; Gkazi, Athina-Soragia; Miller, Jack; Shaw, Christopher E.; Kottlors, Michael; Kirschner, Janbernd; Pestronk, Alan; Li, Yun R.; Ford, Alice Flynn; Gitler, Aaron D.; Benatar, Michael; King, Oliver D.; Kimonis, Virginia E.; Ross, Eric D.; Weihl, Conrad C.; Shorter, James; and Taylor, J. Paul, "Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS" (2013). Wellstone Center for FSHD Publications and Presentations. 7.