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


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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Figure 1: Identification of previously unknown disease mutations in MSP and ALS.
Figure 2: Cytoplasmic pathology of hnRNPA2B1 and hnRNPA1.
Figure 3: The disease mutations affect a PrLD in hnRNPA2B1 and hnRNPA1.
Figure 4: Disease mutations accelerate hnRNPA2 and hnRNPA1 fibrillization.
Figure 5: hnRNPA2 recruitment to stress granules is accelerated by disease mutation.
Figure 6: Mutant hnRNPA2 forms cytoplasmic inclusions in Drosophila.


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We thank the patients whose participation made this work possible. We thank the St Jude Pediatric Cancer Genome Project and J. Zhang in particular for providing access to control sequencing data. We thank C. Gellera, B. Baloh, M. Harms, S. Krause, G. Dreyfuss and T. Cundy for sharing reagents. We thank S. Donkervoort and S. Mumm for coordinating samples, and A. Taylor for editorial assistance. J.P.T. was supported by ALSAC, the Packard Foundation and the National Institutes of Health (NIH) (NS053825); J.P.T. and M.B. were supported by the ALS Association; J.Q.T. was supported by the NIH (AG032953); J.S. was supported by the NIH (DP2OD002177 and NS067354) and the Ellison Medical Foundation; E.D.R. was supported by the National Science Foundation (MCB-1023771). C.C.W. was supported by the NIH (AG031867).

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H.J.K., N.C.K., E.D.R., C.C.W., J.S. and J.P.T. designed experiments. H.J.K., N.C.K., E.A.S., J.Moore, Z.D., K.S.M., B.F., S.L., A.M., A.P.K., Y.R.L. and A.F.F. performed the experiments. K.B.B., A.M.W., R.R., J.L.P., S.A.G., J.Q.T., B.N.S., S.T., A.-S.G., J.Miller, C.E.S., M.K., J.K., A.P., M.B. and V.E.K. provided patient clinical material, clinical evaluation, or evaluation of patient clinical material. H.J.K., N.C.K., Y.-D.W., R.C., B.J.T., A.D.G., O.D.K., E.D.R., J.S. and J.P.T. contributed to data analysis. E.D.R., O.D.K. and C.C.W. contributed to manuscript preparation. H.J.K., J.S. and J.P.T. wrote the manuscript.

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Correspondence to James Shorter or J. Paul Taylor.

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Kim, H., Kim, N., Wang, YD. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467–473 (2013).

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