Journal Article

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

Rademakers, Rosa, Kottlors, Michael, Pinkus, Jack L., Trojanowski, John Q., Li, Yun R., Smith, Bradley N., Wojtas, Aleksandra M., Weihl, Conrad C., Carter, Robert, Ford, Alice Flynn, Kanagaraj, Anderson P., Boylan, Kevin B., Benatar, Michael, Wang, Yong-Dong, Pestronk, Alan, Ross, Eric D., Topp, Simon, Gitler, Aaron D., Shaw, Christopher E., Gkazi, Athina-Soragia, Moore, Jennifer, Traynor, Bryan J., King, Oliver D., Scarborough, Emily A., Diaz, Zamia, Molliex, Amandine, Kim, Hong Joo, Kim, Nam Chul, Kimonis, Virginia E., Taylor, J. Paul, MacLea, Kyle S., Miller, Jack, Li, Songqing, Freibaum, Brian, Greenberg, Steven A., Shorter, James, Kirschner, Janbernd

2013

Overview

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. The identification of pathogenic mutations within prion-like domains (PrLDs) of the RNA-binding proteins hnRNPA2B1 and hnRNPA1 add to our understanding of how mutations in these proteins lead to degenerative disease, and highlight the potential importance of PrLDs in degenerative diseases of the nervous system, muscle and bone. Disease link to prion-like RNA-binding protein How do mutations in RNA-binding proteins cause human disease, and neurodegeneration in particular? Hong Joo Kim et al . have identified mutations in two RNA-binding proteins, hnRNPA2B1 and hnRNPA1, in two families with inclusion body myopathy with frontotemporal dementia. Both of the mutations lie within a highly conserved part of a protein domain that has similarities to prion proteins, and a tendency to aggregate. This aggregation is enhanced by the mutations. The mutated prion-like domain of hnRNPA2 can functionally replace that of a yeast prion protein and reproduce its prion-like behaviour. These findings have relevance to the pathogenesis of degenerative diseases and proteinopathies such as amyotrophic lateral sclerosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/80/304 / Amino Acid Sequence / Amino acids / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Animal models / Animals / Drosophila melanogaster - cytology / Drosophila melanogaster - genetics / Drosophila melanogaster - metabolism / Female / Frontotemporal Dementia - genetics / Frontotemporal Dementia - metabolism / Frontotemporal Dementia - pathology / Genetic testing / Genetics / Genomes / Genomics / HeLa Cells / Heterogeneous-Nuclear Ribonucleoprotein Group A-B - chemistry / Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics / Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism / Humanities and Social Sciences / Humans / Inclusion Bodies - genetics / Inclusion Bodies - metabolism / Inclusion Bodies - pathology / Insects / Male / Mice / Molecular Sequence Data / multidisciplinary / Muscular Dystrophies, Limb-Girdle - genetics / Muscular Dystrophies, Limb-Girdle - metabolism / Muscular Dystrophies, Limb-Girdle - pathology / Mutant Proteins - chemistry / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutation / Mutation - genetics / Myositis, Inclusion Body - genetics / Myositis, Inclusion Body - metabolism / Myositis, Inclusion Body - pathology / Osteitis Deformans - genetics / Osteitis Deformans - metabolism / Osteitis Deformans - pathology / Pathology / Patients / Peptide Termination Factors - chemistry / Peptide Termination Factors - genetics / Peptide Termination Factors - metabolism / Prions - chemistry / Prions - genetics / Prions - metabolism / Protein Structure, Tertiary - genetics / Proteins / RNA - metabolism / Saccharomyces cerevisiae Proteins - chemistry / Saccharomyces cerevisiae Proteins - genetics / Saccharomyces cerevisiae Proteins - metabolism / Science / Software / Yeasts