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

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 & 17 others 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 G Benatar, Oliver D. King, Virginia E. Kimonis, Eric D. Ross, Conrad C. Weihl, James Shorter, J. Paul Taylor

Research output: Contribution to journalArticle

612 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)467-473
Number of pages7
JournalNature
Volume495
Issue number7442
DOIs
StatePublished - Mar 28 2013

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Prions
Mutation
Heterogeneous-Nuclear Ribonucleoproteins
RNA-Binding Proteins
Motor Neurons
Polymerization
Bone and Bones
Muscles
Ribonucleoproteins
Inclusion Bodies
Brain
Neurodegenerative Diseases
Glycine
Seeds
Protein Isoforms
Proteins
Animal Models
Yeasts
Pathology
Amino Acids

ASJC Scopus subject areas

  • General

Cite this

Kim, H. J., Kim, N. C., Wang, Y. D., Scarborough, E. A., Moore, J., Diaz, Z., ... Taylor, J. P. (2013). Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature, 495(7442), 467-473. https://doi.org/10.1038/nature11922

Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. / 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 G; King, Oliver D.; Kimonis, Virginia E.; Ross, Eric D.; Weihl, Conrad C.; Shorter, James; Taylor, J. Paul.

In: Nature, Vol. 495, No. 7442, 28.03.2013, p. 467-473.

Research output: Contribution to journalArticle

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, MG, King, OD, Kimonis, VE, Ross, ED, Weihl, CC, Shorter, J & Taylor, JP 2013, 'Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS', Nature, vol. 495, no. 7442, pp. 467-473. https://doi.org/10.1038/nature11922
Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013 Mar 28;495(7442):467-473. https://doi.org/10.1038/nature11922
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 G ; King, Oliver D. ; Kimonis, Virginia E. ; Ross, Eric D. ; Weihl, Conrad C. ; Shorter, James ; Taylor, J. Paul. / Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. In: Nature. 2013 ; Vol. 495, No. 7442. pp. 467-473.
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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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AU - Scarborough, Emily A.

AU - Moore, Jennifer

AU - Diaz, Zamia

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AU - Li, Yun R.

AU - Ford, Alice Flynn

AU - Gitler, Aaron D.

AU - Benatar, Michael G

AU - King, Oliver D.

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