Webster, C.P., Smith, E.F., Bauer, C.S. et al. (12 more authors) (2016) The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO Journal, 35 (15). pp. 1656-1676.
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 The Authors. Published under the terms of the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/). |
Keywords: | C9orf72; Rab GTPase; amyotrophic lateral sclerosis; autophagy; frontotemporal dementia |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number NATIONAL INSTITUTE FOR HEALTH RESEARCH NF-SI-0512-10082 EUROPEAN COMMISSION - FP6/FP7 EUROMOTOR - 259867 FONDATION DE FRANCE UNSPECIFIED MEDICAL RESEARCH COUNCIL MR/M013251/1 MEDICAL RESEARCH COUNCIL MR/K005146/1 MOTOR NEURONE DISEASE ASSOCIATION Ferraiuolo/Nov14/900-790 SAUDI ARABIAN CULTURAL BUREAU UNSPECIFIED ALZHEIMER'S SOCIETY 260 (AS-PG-15-023) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 12 Jul 2016 14:21 |
Last Modified: | 23 Jun 2023 22:08 |
Published Version: | http://dx.doi.org/10.15252/embj.201694401 |
Status: | Published |
Publisher: | EMBO Press |
Refereed: | Yes |
Identification Number: | 10.15252/embj.201694401 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:101585 |