title: The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy.
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.
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Webster
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Emma F
authors.initials: EF
authors.lastname: Smith
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Bauer
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Annekathrin
authors.initials: A
authors.lastname: Moller
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Guillaume M
authors.identifier: 0000-0002-1621-261X
authors.initials: GM
authors.lastname: Hautbergue
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferraiuolo
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Myszczynska
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Higginbottom
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walsh
authors.affiliation: Department of Biomedical Science, University of Sheffield, Sheffield, UK.
authors.forename: Alexander J
authors.identifier: 0000-0002-1154-6629
authors.initials: AJ
authors.lastname: Whitworth
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Meyer
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grierson
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK k.de_vos@sheffield.ac.uk.
authors.forename: Kurt J
authors.identifier: 0000-0003-2161-6309
authors.initials: KJ
authors.lastname: De Vos
mesh_terms: D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism*; D000073885:C9orf72 Protein; D002468:Cell Physiological Phenomena; D002478:Cells, Cultured; D057180:Frontotemporal Dementia / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D020761:rab1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D000071189:Autophagy-Related Protein-1 Homolog; C484754:ULK1 protein, human; D020761:rab1 GTP-Binding Proteins
keywords: C9orf72; Rab GTPase; amyotrophic lateral sclerosis; autophagy; frontotemporal dementia