The C9orf72 repeat expansion disrupts nucleocytoplasmic transport

Article

关键词: NUCLEAR IMPORT;    SEGREGATION DISTORTION;    GGGGCC REPEAT;    DROSOPHILA;    MUTATIONS;    TDP-43;    GENE;    ALS;    NEURODEGENERATION;    PROTEINS;   

DOI  :  10.1038/nature14973

来源: SCIE

【 摘 要 】

The hexanucleotide repeat expansion (HRE) GGGGCC (G(4)C(2)) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G(4)C(2) RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30G(4)C(2) repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.

【 授权许可】

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