How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other?

Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, are associated with familial amyotrophic lateral sclerosis (ALS). However, little is known about how ALS-causing mutations alter protein-protein and protein-RNA complexes and contribute to neurodegeneration. In this study, we identified protein arginine methyltransferase 1 (PRMT1) as a protein that more avidly associates with ALS-linked FUS-R521C than with FUS-WT (wild type) or FUS-P525L using co-immunoprecipitation and LC-MS analysis. Abnormal association between FUS-R521C and PRMT1 requires RNA, but not methyltransferase activity. PRMT1 was sequestered into cytosolic FUS-R521C-positive stress granule aggregates. Overexpression of PRMT1 rescued neurite degeneration caused by FUS-R521C upon oxidative stress, while loss of PRMT1 further accumulated FUS-positive aggregates and enhanced neurite degeneration. Furthermore, the mRNA of Nd1-L, an actin-stabilizing protein, was sequestered into the FUS-R521C/PRMT1 complex. Nd1-L overexpression rescued neurite shortening caused by FUS-R521C upon oxidative stress, while loss of Nd1-L further exacerbated neurite shortening. Altogether, these data suggest that the abnormal stable complex of FUS-R521C/PRMT1/Nd1-L mRNA could contribute to neurodegeneration upon oxidative stress. Overall, our study provides a novel pathogenic mechanism of the FUS mutation associated with abnormal protein-RNA complexes upon oxidative stress in ALS and provides insight into possible therapeutic targets for this pathology.

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“…3A), which are involved in RNA recruitment and arginine methylation of RNA binding proteins293031. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress

Jun

Ryu

Jun

et al. 2017

Sci Rep

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“…Accumulating evidence suggests that TDP-43 proteinopathy mediates motor neuron degeneration in familial ALS caused by diverse genetic defects in ubiquilin 2, profilin 1, optineurin, valosin-containing protein, and C9ORF72 (reviewed in Ref. 3). Moreover, the presence of mutations in TDP-43 in a subpopulation of familial ALS indicates its primary role in ALS pathogenesis (4).…”

Section: Cells Overexpressing the Rrm1-c/s Tdp-43 With Antibody Targementioning

confidence: 99%

Aberrant Assembly of RNA Recognition Motif 1 Links to Pathogenic Conversion of TAR DNA-binding Protein of 43 kDa (TDP-43)

Shodai

Morimura

Ido

et al. 2013

Journal of Biological Chemistry

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Background:The role of RRM1 in the pathogenesis of TDP-43 proteinopathy is unclear. Results: RRM1 was aggregate-prone, mediated by a self-assembly at newly identified amyloidogenic ␤-strands containing cysteines; cysteine substitution(s) replicated diverse cytopathologies of TDP-43 in ALS. Conclusion: RRM1 misfolding may underlie TDP-43 proteinopathy. Significance: This study proposes a novel mechanism and a new in vitro model for TDP-43 proteinopathy.

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“…Editing is implicated in an expanding list of diseases, including breast cancer 54 , suicidal depression 55 and amyotrophic lateral sclerosis (ALS). Substantial evidence points toward ADAR2 misregulation in motor neurons of ALS patients 56 , and recent identification of a hexanucleotide repeat associated with ALS 57 has strengthened the hypothesis that aberrant RNA processing is involved in ALS, possibly through the sequestration of RNAbinding proteins, such as ADAR, with irregular transcripts in inclusion bodies 58 .…”

Section: Nature Communications | Doimentioning

confidence: 99%

Tertiary structural elements determine the extent and specificity of messenger RNA editing

et al. 2013

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The specificity and extent of RNA editing by ADAR enzymes is determined largely by local primary sequence and secondary structural imperfections in duplex RNA. Here we surgically alter conserved cis elements associated with a cluster of ADAR modification sites within the endogenous Drosophila paralytic transcript. In addition to the local requirement for a central imperfect RNA duplex containing the modified adenosines, we demonstrate that a secondary RNA duplex containing splicing signals strongly modulates RNA editing. A subtle non-coding mutation, extending base pairing of this accessory helix, confers significant phenotypic consequences via effects on splicing. Through mutation/counter-mutation, we also uncover and functionally replace a highly conserved intronic long-range tertiary pseudoknot that is absolutely required for deamination of one particular adenosine in the central duplex. Our results demonstrate that complex RNA tertiary structures, which may be difficult to predict computationally, form in vivo and can regulate RNA-editing events.

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How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other?

Abstract: Recent discoveries point to an unprecedented convergence of molecular pathways in ALS and FTLD involving RNA metabolism. Defining the exact points of convergence will likely be key to advancing therapeutics development in the coming years.

Cited by 30 publications

References 86 publications

Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress

Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress

Aberrant Assembly of RNA Recognition Motif 1 Links to Pathogenic Conversion of TAR DNA-binding Protein of 43 kDa (TDP-43)

Tertiary structural elements determine the extent and specificity of messenger RNA editing

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