Disease mutations in the prion-like domains of hnRNPA1 and hnRNPA2/B1 introduce potent steric zippers that drive excess RNP granule assembly

Abstract

Approximately 1% of human proteins harbor a prion-like domain (PrLD) of similar low complexity sequence and amino acid composition to domains that drive prionogenesis of yeast proteins like Sup35. PrLDs are over-represented in human RNA-binding proteins and mediate phase transitions underpinning RNP granule assembly. This modality renders PrLDs prone to misfold into conformers that accrue in pathological inclusions that characterize various fatal neurodegenerative diseases. For example, TDP-43 and FUS form cytoplasmic inclusions in amyotrophic lateral sclerosis (ALS) and mutations in TDP-43 and FUS can cause ALS. Here, we review our recent discovery of discrete missense mutations that alter a conserved gatekeeper aspartate residue in the PrLDs of hnRNPA2/B1 and hnRNPA1 and cause multisystem proteinopathy and ALS. The missense mutations generate potent steric zippers in the PrLDs, which enhance a natural propensity to form self-templating fibrils, promote recruitment to stress granules and drive cytoplasmic inclusion formation. PrLDs occur in ~250 human proteins and could contribute directly to the etiology of various degenerative disorders.

Keywords: :

• amyotrophic lateral sclerosis
• hnRNPA1
• hnRNPA2/B1
• multisystem proteinopathy
• prion
• prion-like domain

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Disclosure of Potential Conflicts of Interest

No potential conflict of interest was disclosed.

Acknowledgments

We thank the patients whose participation made this work possible. J.S. was supported by the NIH (DP2OD002177 and NS067354), the Packard Center for ALS Research at Johns Hopkins University and the Ellison Medical Foundation. J.P.T. was supported by ALSAC, the Packard Center for ALS Research at Johns Hopkins University, the ALS Association and the National Institutes of Health (NIH) (NS053825).