. Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients. Cell Rep. 2017 Jun 13;19(11):2244-2256. PubMed.


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  1. Toxicity of dipeptide repeat proteins (DPRs) has been repeatedly demonstrated in models of disease associated with G4C2-repeat expansion of C9ORF72. The question of how that toxicity is mediated has been harder to elucidate but several lines of evidence have converged on disruption of mRNA splicing. In this paper, the group of Robin Reed goes a step further and attempts to define a specific mechanism. They propose that a key event is disturbed function of the U2 snRNP complex. Several observations support this hypothesis: demonstration of DPR binding to U2 snRNP components in vitro; cytoplasmic mislocalization of U2 snRNP components in C9ORF72 cell models; and enrichment of U2-mediated splicing events in aberrant splicing observed in C9ORF72 models. This is very interesting and provides a number of testable hypotheses.

    However, as the authors acknowledge, there are some limitations to their data, for example, splicing assays shown depend on supra-physiological concentrations of DPRs. Most pointedly, although U2-mediated splicing events are enriched in C9ORF72 models, the majority of aberrant splicing in these models is U2-independent. Similarly, although U2 snRNP complex components are enriched in DPR binding partners, the majority of binding partners (including other splicing proteins) are not components of the U2 snRNP.

    In short, the authors provide evidence for a mechanism but it does not appear to capture all of the interactions they describe, and the relative importance to neurotoxicity is uncertain. Addressing this is important before commencing development of therapeutics. One way to do this might be to examine correlations with clinical phenotype. We have previously shown that splicing error rate correlates with disease severity in C9ORF72-patient derived cells (Cooper-Knock et al., 2015); it would be fascinating to know if this correlation was strengthened when splicing events were limited to U2-mediated events.

    The final observation I would make, which applies to more than just this study, is that currently (given the tools available), abundance of the DPRs studied—PR and GR—does not correlate with neurodegeneration in patient postmortem tissue (Davidson et al., 2016) despite their toxicity in cell and animal models. Moreover, GR and PR are relatively absent from important populations such as postmortem motor neurons in ALS patients. This is an important unsolved puzzle for the field. 


    . C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis. PLoS One. 2015;10(5):e0127376. Epub 2015 May 27 PubMed.

    . Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins. Neuropathol Appl Neurobiol. 2016 Apr;42(3):242-54. Epub 2015 Dec 7 PubMed.

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  1. When C9ORF72 Silences U2, Spliceosomes Can’t Find What They’re Looking For