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

Boston Biomedical Research Institute, 64 Grove St., Watertown, MA 02472, USA.
Brain research (Impact Factor: 2.84). 01/2012; 1462:61-80. DOI: 10.1016/j.brainres.2012.01.016
Source: PubMed

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 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. This article is part of a Special Issue entitled RNA-Binding Proteins.

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    • "The high propensity of TDP-43 and FUS to aggregate is linked to the presence of a glycine-rich domain in both proteins, namely in the N-terminal part of FUS (amino acids 1–239) and the C-terminal part of TDP-43 (amino acids 274–414). Such domains, which are frequently found in RNA-binding proteins, have similar amino acid composition with yeast prion proteins and are therefore also called " prion-like " (Cushman et al., 2010), or low complexity domains (Kato et al., 2012), and can acquire disordered structures upon protein folding (King et al., 2012). "
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    ABSTRACT: Propagation of pathological protein assemblies via a prion-like mechanism has been suggested to drive neurodegenerative diseases, such as Parkinson's and Alzheimer's. Recently, amyotrophic lateral sclerosis (ALS)-linked proteins, such as SOD1, TDP-43 and FUS were shown to follow self-perpetuating seeded aggregation, thereby adding ALS to the group of prion-like disorders. The cell-to-cell spread of these pathological protein assemblies and their pathogenic mechanism is poorly understood. However, as ALS is a non-cell autonomous disease and pathology in glial cells was shown to contribute to motor neuron damage, spreading mechanisms are likely to underlie disease progression via the interplay between affected neurons and their neighboring glial cells.
    Virus Research 02/2015; 8. DOI:10.1016/j.virusres.2014.12.032 · 2.32 Impact Factor
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    • "identify prion-like domains, both FUS and TDP43, ranked highly (1st and 10th, respectively) among RNA-binding proteins harboring a canonical RNA recognition motif and a putative prion domain [30]. This prion-like domain has been recently implicated in TDP43 and FUS toxic misfolding and aggregation in vitro [31]. "
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    ABSTRACT: Genetic discoveries in ALS have a significant impact on deciphering molecular mechanisms of motor neuron degeneration. The identification of SOD1 as the first genetic cause of ALS led to the engineering of the SOD1 mouse, the backbone of ALS research, and set the stage for future genetic breakthroughs. In addition, careful analysis of ALS pathology added valuable pieces to the ALS puzzle. From this joint effort, major pathogenic pathways emerged. Whereas the study of TDP43, FUS and C9ORF72 pointed to the possible involvement of RNA biology in motor neuron survival, recent work on P62 and UBQLN2 refocused research on protein degradation pathways. Despite all these efforts, the etiology of most cases of sporadic ALS remains elusive. Newly acquired genomic tools now allow the identification of genetic and epigenetic factors that can either increase ALS risk or modulate disease phenotype. These developments will certainly allow for better disease modeling to identify novel therapeutic targets for ALS. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 09/2014; 1852(4). DOI:10.1016/j.bbadis.2014.08.010 · 4.88 Impact Factor
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    • "Recent researches have indicated TDP-43 C-terminus (277–414) as a prion-like domain which played a critical role in TDP-43 pathogenesis [24]–[26]. To obtain further insights in whether TDP-43 C-terminus mutant peptides may possess prion property as PrPsc (scrapie isoform of prion protein) in membrane disruption, we applied calcein leakage assay to monitor the membrane permeability in the presence and absence of different peptides. "
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    ABSTRACT: TAR DNA-binding protein (TDP-43) was identified as the major ubiquitinated component deposited in the inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in 2006. Later on, numerous ALS-related mutations were found in either the glycine or glutamine/asparagine-rich region on the TDP-43 C-terminus, which hinted on the importance of mutations on the disease pathogenesis. However, how the structural conversion was influenced by the mutations and the biological significance of these peptides remains unclear. In this work, various peptides bearing pathogenic or de novo designed mutations were synthesized and displayed their ability to form twisted amyloid fibers, cause liposome leakage, and mediate cellular toxicity as confirmed by transmission electron microscopy (TEM), circular dichroism (CD), Thioflavin T (ThT) assay, Raman spectroscopy, calcein leakage assay, and cell viability assay. We have also shown that replacing glycines with prolines, known to obstruct β-sheet formation, at the different positions in these peptides may influence the amyloidogenesis process and neurotoxicity. In these cases, GGG308PPP mutant was not able to form beta-amyloid, cause liposome leakage, nor jeopardized cell survival, which hinted on the importance of the glycines (308-310) during amyloidogenesis.
    PLoS ONE 08/2014; 9(8):e103644. DOI:10.1371/journal.pone.0103644 · 3.23 Impact Factor
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