期刊
EMBO JOURNAL
卷 35, 期 15, 页码 1656-1676出版社
WILEY
DOI: 10.15252/embj.201694401
关键词
amyotrophic lateral sclerosis; autophagy; C9orf72; frontotemporal dementia; Rab GTPase
资金
- Thierry Latran Foundation (Project RoCIP)
- Medical Research Council (MRC) [MR/K005146/1, MR/M013251/1]
- Alzheimer's Society [260 (AS-PG-15-023)]
- University of Sheffield Moody Family Endowment
- EU Framework 7 Award [259867]
- NIHR Senior Investigator
- Motor Neurone Disease Association Prize Studentship [DeVos/Oct13/870-892]
- Marie Curie International Fellowship (EU framework 7 grant) [303101]
- MRC [MC_UP_1501/1, MR/M013251/1, MR/K005146/1, MR/M010864/1] Funding Source: UKRI
- Medical Research Council [MC_UP_1501/1, MR/M013251/1, MR/M010864/1, MR/K005146/1] Funding Source: researchfish
- Motor Neurone Disease Association [DeVos/Oct13/870-792] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10082] Funding Source: researchfish
A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). C9orf72 encodes two C9orf72 protein isoforms of unclear function. Reduced levels of C9orf72 expression have been reported in C9ALS/FTD patients, and although C9orf72 haploinsufficiency has been proposed to contribute to C9ALS/FTD, its significance is not yet clear. Here, we report that C9orf72 interacts with Rab1a and the Unc-51-like kinase 1 (ULK1) autophagy initiation complex. As a Rab1a effector, C9orf72 controls initiation of autophagy by regulating the Rab1a-dependent trafficking of the ULK1 autophagy initiation complex to the phagophore. Accordingly, reduction of C9orf72 expression in cell lines and primary neurons attenuated autophagy and caused accumulation of p62-positive puncta reminiscent of the p62 pathology observed in C9ALS/FTD patients. Finally, basal levels of autophagy were markedly reduced in C9ALS/FTD patient-derived iNeurons. Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.
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