Cited by 405Amyotrophic Lateral Sclerosis ResearchAutophagy in Disease and TherapyAlzheimer's disease research and treatments

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The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy

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Webster, Christopher P, Smith, Emma F, Bauer, Claudia S, Moller, Annekathrin, Hautbergue, Guillaume M, Ferraiuolo, Laura, Myszczynska, Monika A, Higginbottom, Adrian, Walsh, Matthew J, Whitworth, Alexander J, Kaspar, Brian K, Meyer, Kathrin, Shaw, Pamela J, Grierson, Andrew J, De Vos, Kurt J·2016·The EMBO Journal

DOI 10.15252/embj.201694401PMC PMC4969571

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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. C9ALS/FTD‐associated C9orf72 is a Rab1a effector that controls initiation of autophagy by regulating ULK1 complex trafficking. Disruption of C9orf72 function inhibits autophagy and mimics the p62 pathology found in C9ALS/FTD patients. C9ALS/FTD iNeurons display reduced autophagy. ALS/FTD‐associated C9orf72 is a Rab1a effector that controls initiation of autophagy by regulating ULK1 complex trafficking.

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Authors: Webster, C. P., Smith, E. F., Bauer, C. S., Moller, A., Hautbergue, G. M., Ferraiuolo, L., Myszczynska, M. A., Higginbottom, A., Walsh, M. J., Whitworth, A. J., Kaspar, B. K., Meyer, K., Shaw, P. J., Grierson, A. J., & De Vos, K. J.
Affiliations: University of Sheffield (GB)
Nationwide Children's Hospital (US)
ORCID: Webster, Christopher P
Hautbergue, Guillaume M
Ferraiuolo, Laura
Myszczynska, Monika A
Whitworth, Alexander J
Kaspar, Brian K
Meyer, Kathrin
Shaw, Pamela J
Grierson, Andrew J
De Vos, Kurt J
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2016-06-22
Volume: 35
Issue: 15
Pages: 1656-1676
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.15252/embj.201694401
PMC: PMC4969571
OpenAlex: W2467513012
Cited by: 404
References: 75
Citations by year: 2026: 24 · 2025: 25 · 2024: 35 · 2023: 36 · 2022: 29 · 2021: 50 · 2020: 55 · 2019: 47 · 2018: 46 · 2017: 43 · 2016: 13
FWCI: 37.35
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
Locations: The EMBO Journal (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Funders: Thierry Latran Foundation (RoCIP)
Medical Research Council (MR/K005146/1, MR/M013251/1)
Alzheimer's Society (260 (AS‐PG‐15‐023))
University of Sheffield (Moody Family Endowment)
European Union Seventh Framework Programme (EuroMOTOR 259867, 303101)
Motor Neurone Disease Association (DeVos/Oct13/870‐892)
Topics: Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords: C9orf72, Rab1A, ULK1 complex, autophagy initiation, amyotrophic lateral sclerosis, frontotemporal dementia, haploinsufficiency, phagophore, induced neurons, protein isoforms
MeSH terms: Autophagy-Related Protein-1 Homolog, C9orf72 Protein, Autophagy, Cell Physiological Phenomena, Cells, Cultured, Humans, Neurons, Proteins, rab1 GTP-Binding Proteins, Intracellular Signaling Peptides and Proteins, Frontotemporal Dementia

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The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy

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