Woerner AC, Frottin F, Hornburg D, Feng LR, Meissner F, Patra M, Tatzelt J, Mann M, Winklhofer KF, Hartl FU, Hipp MS. Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science. 2016 Jan 8;351(6269):173-6. Epub 2015 Dec 3 PubMed.
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I think this paper provides nice mechanistic insight into the nuclei-cytoplasmic transport defects that my paper and the Rothstein Nature paper demonstrated (Freibaum et al., 2015; Zhang et al., 2015) and further suggests that protein rather than RNA toxicity might be the more important factor in C9orf72-mediated neurotoxicity. The mislocalization of THOC2 and the suggestion of RNA processing defects in disease is consistent with our identification of THOC4(ALYREF), the nuclear cap binding complex (NCBP1, NCBP2, ARS2), and exosomal subunits as genetic interactors of C9orf72 mediated toxicity.
References:
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 Sep 3;525(7567):129-33. Epub 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 Sep 3;525(7567):56-61. Epub 2015 Aug 26 PubMed.
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