The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease

Abstract

Prions are self-templating protein conformers that are naturally transmitted between individuals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable ‘prion domain’ enriched in asparagine, glutamine, tyrosine and glycine residues unifies the majority of yeast prion proteins. Deletion of this domain precludes prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An algorithm designed to detect prion domains has successfully identified 19 domains that can confer prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA-binding prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer’s disease and Huntington’s disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. Recently, perturbed RNA-binding proteostasis of TAF15, which is the 2nd ranked RRM-bearing prion candidate, has been connected with ALS and FTLD-U. We strongly suspect that we have now merely reached the tip of the iceberg. We predict that additional RNA-binding prion candidates identified by our algorithm will soon surface as genetic modifiers or causes of diverse neurodegenerative conditions. Indeed, simple prion-like transfer mechanisms involving the prion-like domains of RNA-binding proteins could underlie the classical non-cell-autonomous emanation of neurodegenerative pathology from originating epicenters to neighboring portions of the nervous system.

Tau protein liquid–liquid phase separation can initiate tau aggregation

“…Tau is an exceptionally soluble protein, and the molecular mechanisms that link soluble tau to aggregated tau are unknown. We now report that tau—similar to several other neurodegenerative disease‐associated proteins such as the prion‐domain harboring RNA binding proteins FUS, TDP43, hnRNPA1 (King et al , 2012)—can undergo liquid–liquid phase separation (LLPS), and we suggest that this observation may provide a biological mechanism for tau aggregation in neurodegenerative diseases.…”

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

“…Low‐complexity domains with yeast prion‐like sequence composition are emerging as primary drivers of protein inclusion formation and are frequently the sites of disease‐causing missense mutations (King et al , 2012). However, it is unclear how the cell limits the aggregation propensity of these domains and if therapies targeting these domains could be developed.…”

“…Note that yeast prion and mammalian prion‐like domains have no sequence resemblance nor homology to the mammalian PrP prion associated with “mad cow disease”. Human prion‐like domains have emerged as primary drivers of cytoplasmic protein aggregation in neurodegenerative disease and are also sites of mutations in genetic forms of these conditions (King et al , 2012). Importantly, mammalian domains categorized as prion‐like are not homologous to yeast prions, but do contain amino acids such as serine, threonine, and tyrosine, which are potential targets of cellular phosphorylation.…”

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

“…The RNA-binding ability of TDP43, hnRNP A1, and hnRNP A2/B1 may be key to the propagation of neurodegeneration, as RNA is a potent and necessary cofactor for the conversion of the mammalian prion protein PrP C into its pathogenic isoform, PrP Sc [128]. Confirming the connection between neurodegeneration and prion-like behavior of RNA-binding proteins, algorithms designed to identify proteins harboring prion-like domains revealed an enrichment of RNA binding proteins [28,31], many of which have since been implicated in ALS and FTLD pathogenesis [30,129].…”

“…The identification of neuronal cytoplasmic inclusions rich in the RNA-binding protein transactive response element DNA/RNA binding protein of 43 kDa (TDP43) provided an important link between two of these mechanisms-protein aggregation and RNA dysfunction [6,7]. TDP43-positive inclusions are a hallmark of sporadic ALS (sALS) and the majority of fALS [6,7,25,26], and mutations in the genes encoding TDP43 (TARDBP) and related RNA binding proteins [15,16,19,27,28] cause fALS, emphasizing the critical importance of RNA processing to the pathogenesis of both sALS and fALS. TDP43 is a member of the heterogenous nuclear ribonuclear protein (hnRNP) family of RNA binding proteins that have diverse and integral functions in RNA metabolism and homeostasis [29].…”