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

By Oliver D. King, Aaron Gitler, J. Shorter. Brain Research, 2012

630 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/5e59be8937508a691b1df406808dab3bc5ca14a8

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

In Neurology

Citations in the corpus

Distinct stages in stress granule assembly and disassembly (2016, background): “Since IDR-containing proteins are enriched in stress granules and other mRNP granules (Decker et al., 2007; Gilks et al., 2004; Jain et al., 2016; Kato et al., 2012; King et al., 2012; Reijns et al., 2008), this has led to the suggestion that IDRs on mRNA binding proteins form hetero-”
Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, neutral): “TDP-43 and FUS/TLS Reshape ALS and FTD TDP-43 Mutation and Pathology in ALS and FTD TDP-43 is a 414 amino acid protein containing two RNA recognition motifs (RRMs) followed by a glycine-rich, low-sequence complexity prion-like domain (Kato et al., 2012; King et al., 2012).”
Tau protein liquid–liquid phase separation can initiate tau aggregation (2018, neutral): “…— 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…”
PLAAC: a web and command-line application to identify proteins with prion-like amino acid composition (2014, methodology): “This algorithm and extensions have since been used in several studies to identify prion-like sequences in yeast (Holmes et al ., 2013) and also in humans (Kim et al. , 2013; King et al. , 2012), in which several proteins with PrLDs are associated with ALS and related neurodegenerative disorders.”
Intrinsically disordered regions contribute promiscuous interactions to RNP granule assembly (2017, background): “However, IDRs are enriched in RNP granule proteins (Decker et al., 2007; Jain et al., 2016; Kato et al., 2012; King et al., 2012; Reijns et al., 2008), and IDRs can play a role in RNP granule assembly (e.g. Decker et al., 2007; Gilks et al., 2004; Wang et al., 2014).”
RNA controls PolyQ protein phase transitions (2015, background): “It is then not surprising that a large number of IDP/LCScontaining (or prion-like, aggregation-prone domain-containing) RNA-binding proteins are associated with neurodegenerative diseases (King et al., 2012).”
Stress granules as crucibles of ALS pathogenesis (2013, background): “These domains are typically enriched in uncharged polar amino acids (such as asparagine, glutamine, and tyrosine) and glycine (Alberti et al., 2009; King et al., 2012).”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, background): “This unusual composition resembles the prion-like domains of several yeast proteins, such as Sup35, Rnq1, and Cyc8 etc. (Patel et al., 2009; King et al., 2012; Liebman and Chernoff, 2012).”
Formation and Maturation of Phase Separated Liquid Droplets by RNA Binding Proteins (2015, background): “, 2007), but also include those containing repeated G/S-F/Y-G/S motifs (Kato et al., 2012; Nott et al., 2015; Updike et al., 2011; King et al., 2012; Sun et al., 2011).”
Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity (2017, neutral): “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).”
ALS mutations disrupt phase separation mediated by -helical structure in the TDP-43 low complexity C-terminal domain (2016, background): “classified as “prion-like” due to a low complexity composition rich in polar and poor in aliphatic and charged residues, resembling the amino acid frequency in yeast prion domains(King et al., 2012).”
A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins (2018, neutral): “…the phase separation properties of a class of intrinsically disordered scaffold proteins that we refer to as ‘‘FUS family proteins,’’ because they share similar domain structures, and the first described member of this family was Fused in Sarcoma, or FUS (Crozat et al., 1993; King et al., 2012).”
Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II (2015, neutral): “…of these proteins, including 29 found in humans, contains a disordered domain rich in polar and aromatic residues and nearly devoid of aliphatic and charged amino acids, resembling the aggregation-prone glutamine/asparagine-rich domains of yeast prion proteins such as Sup35 (King et al., 2012).”
A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. (2015, neutral): “Prion-like LC domains are particularly abundant in RNA-and DNA-binding proteins and have been conserved across evolution (Kim et al., 2013; King et al., 2012; Malinovska et al., 2013).”