期刊
NATURE NEUROSCIENCE
卷 19, 期 12, 页码 1610-1618出版社
NATURE PORTFOLIO
DOI: 10.1038/nn.4407
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资金
- European Community [259867]
- Hermann-und-Lilly Schilling Stiftung im Stifterverband der Deutschen Industrie
- Deutsche Gesellschaft fur Muskelerkrankungen [IBC He 2/2]
- Bavarian Excellence Program ForIPS
- DFG [SPP 1738]
- MeDDrive of the Medical Faculty of the Technische Universitat Dresden
- BIOCREA GmbH
- Helmholtz Virtual Institute program RNA Dysmetabolism in ALS
- NOMIS Foundation
- FTD [VI-510]
- family of a deceased ALS patient
- Medical Research Council [MR/M010864/1] Funding Source: researchfish
- MRC [MR/M010864/1] Funding Source: UKRI
Intronic hexanucleotide expansions in C9ORF72 are common in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but it is unknown whether loss of function, toxicity by the expanded RNA or dipeptides from non-ATG-initiated translation are responsible for the pathophysiology. We determined the interactome of C9ORF72 in motor neurons and found that C9ORF72 was present in a complex with cofilin and other actin binding proteins. Phosphorylation of cofilin was enhanced in C9ORF72-depleted motor neurons, in patient-derived lymphoblastoid cells, induced pluripotent stem cell-derived motor neurons and post-mortem brain samples from ALS patients. C9ORF72 modulates the activity of the small GTPases Arf6 and Rac1, resulting in enhanced activity of LIM-kinases 1 and 2 (LIMK1/2). This results in reduced axonal actin dynamics in C9ORF72-depleted motor neurons. Dominant negative Arf6 rescues this defect, suggesting that C9ORF72 acts as a modulator of small GTPases in a pathway that regulates axonal actin dynamics.
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