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

Abstract

SummaryAlgorithms designed to identify canonical yeast prions predict that ~250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor 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 hnRNPA2/B1 and hnRNPA1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and a case of familial ALS. Wild-type hnRNPA2 and hnRNPA1 display 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 formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Importantly, 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 must be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

The phenotypic variability of amyotrophic lateral sclerosis

“…Mutations in VCP, HNRNPA2B1 and HNRNPA1 can induce ALS and/or FTLD combined with inclusion body myositis and bone abnormalities, such as those seen in Paget disease. 72,73 These phenotypes again demonstrate the multisystemic character of ALS.…”

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

“…We thus examined phase separation of full‐length FUS, 6E, and 12E by monitoring changes in morphology of protein assemblies over longer time periods or with orbital agitation (Fig 2E), using a method adapted from a protocol previously shown to induce fibrillization of hnRNPA2B1 and hnRNPA1 (Kim et al , 2013). Non‐agitated FUS, 6E, and 12E formed similar liquid‐like droplets, as observed by DIC microscopy up to 1 day after cleavage from the solubility tags (Fig 2E).…”

“…However, the high local concentration of proteins in RNP granules formed by LLPS may potentiate the conversion of liquid compartments into solid cytoplasmic aggregates and inclusions observed in disease (Murakami et al , 2015; Patel et al , 2015). This phenomenon may be enhanced by mutations in disease‐associated ribonuclear proteins that increase their cytoplasmic concentration (Vance et al , 2013) or aggregation propensity (Kim et al , 2013). …”

Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans

“…Interestingly, both Hnrnpa2b1 and Hnrnpa1 are known to be determinants of lifespan in Drosophila species, by virtue of their regulation of the TDB‐43 protein (Romano et al ., 2014). TDB‐43 is crucial in fruit flies for correct splicing and regulation of mRNA stability and is associated with amyotrophic lobar sclerosis and frontotemporal lobar degeneration in humans (Neumann et al ., 2007; Kim et al ., 2013). Mutations have also been described in age‐related diseases such as Alzheimer's, Parkinson's and Huntington's diseases (Baloh, 2011).…”