Blocking SRSF1-Mediated Nuclear Export May Protect Motor Neurons in C9orf72 ALS

Imports and exports. Blocking SRSF1-dependent nuclear export may help protect motor neurons in C9orf72 ALS by reducing levels of expanded repeat RNAs that reach the cytoplasm. [Courtesy of Hautberge et al., 2017, Human Molecular Genetics under CC-BY-4.0 license].

A new treatment strategy may help protect motor neurons in C9orf72 ALS according to a new study led by University of Sheffield’s Pamela Shaw in England. The study found that depleting the SR protein SRSF1 blocked the nuclear export of expanded repeat transcripts in a neuronal cell model of the disease, reducing the synthesis of C9orf72 ALS-associated dipeptide repeat proteins. What’s more, this approach protected motor neurons against toxicity mediated by patient-derived C9orf72 ALS astrocytes (iAstrocytes) in co-culture. 

The findings build on previous studies led by St Jude’s J. Paul Taylor in Tennessee and Johns Hopkins University’s Jeff Rothstein in Maryland, which found that the loss of key components of the nuclear export machinery reduced toxicity in a Drosophila model of C9orf72 ALS (see August 2015 news).

The study is published on July 5 in Nature Communications.

Efforts to target nuclear export of expanded repeat RNAs in C9orf72 ALS are now underway (see July 2017 news). Stay tuned.


To learn about other emerging treatment strategies for C9orf72 ALS, including those approaching the clinic, check out: A New Model of C9orf72 ALS Cycles In.

Featured Paper

Hautbergue GM, Castelli LM, Ferraiuolo L, Sanchez-Martinez A, Cooper-Knock J, Higginbottom A, Lin YH, Bauer CS, Dodd JE, Myszczynska MA, Alam SM, Garneret P, Chandran JS, Karyka E, Stopford MJ, Smith EF, Kirby J, Meyer K, Kaspar BK, Isaacs AM, El-Khamisy SF, De Vos KJ, Ning K, Azzouz M, Whitworth AJ, Shaw PJ. SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nat Commun. 2017 Jul 5;8:16063. [PubMed].


Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015 Aug 26; [PubMed].

Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Aug 26; [PubMed].

Jovičić A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, Kramer NJ, Gage FH, Van Den Bosch L, Robberecht W, Gitler AD. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci. 2015 Aug 26;18(9):1226-9.[PubMed].


c9orf72 dipeptide repeat proteins disease-als disease-ftd nuclear export topic-preclinical topic-randd
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