. SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nat Commun. 2017 Jul 5;8:16063. PubMed.


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  1. This is an important paper. It highlights the importance of SRSF1 in regulating the transport of mutant C9ORF72 transcripts from the nucleus to the cytoplasm. SR proteins are best known for their effects in regulating splicing, with more recent data indicating that SR proteins are also critical for nucleocytoplasmic transport of select RNAs, thereby linking splicing and trafficking. By blocking SRSF1-dependent nucleocytoplasmic transport, the authors were able to prevent C9ORF72 neurotoxicity or pathology in a variety of models (Drosophila, mouse cultures, human cultures). By blocking transport, the translation of mutant transcripts into dipeptide repeat proteins is abrogated.

    The lifecycle of mutant C9ORF72 transcripts is just beginning to be understood, from transcription, splicing, trafficking, translation, and degradation. Understanding each of these processes on a basic level will likely lead to several potentially therapeutic targets. 

    Whether SRSF1 itself (or the interaction between SRSF1 and the nuclear export factor, NSF1) represents a viable therapeutic target will require additional studies to determine whether SRSF1 inhibition is specific enough to be therapeutic in the absence of excess toxicity.

    There are approximately 100,000 to 200,000 SRSF1 binding sites in the transcriptome. Knockdown of SRSF1 leads to differential nuclear export of 225 transcripts, results in differential expression of ~500 transcripts (mostly coding transcripts), and apparently causes altered splicing of >2,500 transcripts (Müller-McNicoll et al., 2016). Therefore, finding an appropriate therapeutic range may be difficult. However, given the absence of any therapy for C9ORF72-related ALS and FTD, all potential therapeutic targets should be rigorously tested before any final judgements are made.


    . SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export. Genes Dev. 2016 Mar 1;30(5):553-66. PubMed.

    View all comments by Edward B. Lee
  2. We agree with Edward B. Lee that care must be taken when manipulating the expression levels of SRSF1, and we cite the important study by Müller-McNicoll et al., 2016, in our manuscript. However, neuroprotection in our neuronal cell and Drosophila models of C9ORF72-related disease was achieved with moderate depletion of SRSF1 (60-70 percent) compared to a more than 90 percent depletion in the Müller-McNicoll et al., 2016, study.

    This study, and others such as Hautbergue et al., 2009, clearly indicated that single depletion of nuclear export adaptors has moderate effects on the nuclear export of bulk mRNAs and cellular homeostasis in human due to functional compensation.

    On the other hand, we  also showed that expression of an engineered mutant of SRSF1 that is sequestered on pathological C9ORF72-repeat transcripts, but is unable to interact with NXF1 and the nuclear export machinery, also confers neuroprotection similarly to the partial depletion of SRSF1. This constitutes an alternative therapeutic strategy, which will allow avoiding manipulating the endogenous expression levels of SRSF1.

    We are currently developing gene therapy programs in a preclinical mouse model of C9ORF72-related disease to test the efficacy and safety of both the partial depletion of SRSF1 and the exogenous expression of the engineered SRSF1 mutant.


    . UIF, a New mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA. Curr Biol. 2009 Dec 1;19(22):1918-24. PubMed.

    View all comments by Guillaume Hautbergue

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  1. Barring Export of Expanded Repeat RNAs Tames Their Toxicity