Guo Q, Lehmer C, Martínez-Sánchez A, Rudack T, Beck F, Hartmann H, Pérez-Berlanga M, Frottin F, Hipp MS, Hartl FU, Edbauer D, Baumeister W, Fernández-Busnadiego R. In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment. Cell. 2018 Feb 8;172(4):696-705.e12. Epub 2018 Feb 1 PubMed.

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  1. This is an excellent study, which shows direct impairment of proteasome by Poly-GA aggregates. Most of ALS/FTD-related molecules belong to two intracellular machineries involved in RNA regulation and protein quality control systems (Ito et al., 2017). Mutants in the latter (including p62, optineurin, TBK1, UBQLN2, VCP/p97, and CCNF) are assumed to lead to dysfunction of the proteasome and/or of autophagy, resulting in the accumulation of RNA-binding proteins, such as TDP-43, and hence RNA dysregulation. Therefore, this finding is strong evidence indicating a link between dipeptide repeat proteins and TDP-43 proteinopathy in C9 brain.

    References:

    Ito D, Hatano M, Suzuki N. RNA binding proteins and the pathological cascade in ALS/FTD neurodegeneration. Sci Transl Med. 2017 Nov 8;9(415) PubMed.

    View all comments by Daisuke Ito

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  1. Are ALS Dipeptide Repeat Ribbons Entangling Proteasomes?