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Rare Dis. 2013 May 29;1:e25200. doi: 10.4161/rdis.25200. eCollection 2013.

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

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Department of Biochemistry and Biophysics; Perelman School of Medicine at The University of Pennsylvania; Philadelphia, PA USA.
Department of Developmental Neurobiology; St Jude Children's Research Hospital; Memphis, TN USA.


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.


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

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