Premium
The C9orf72 protein interacts with Rab1a and the ULK 1 complex to regulate initiation of autophagy
Author(s) -
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
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201694401
Subject(s) - c9orf72 , haploinsufficiency , autophagy , biology , microbiology and biotechnology , amyotrophic lateral sclerosis , effector , frontotemporal dementia , neurite , trinucleotide repeat expansion , cancer research , gene , genetics , phenotype , allele , pathology , medicine , apoptosis , in vitro , disease , dementia
A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9 ALS / FTD ). C9orf72 encodes two C9orf72 protein isoforms of unclear function. Reduced levels of C9orf72 expression have been reported in C9 ALS / FTD patients, and although C9orf72 haploinsufficiency has been proposed to contribute to C9 ALS / FTD , its significance is not yet clear. Here, we report that C9orf72 interacts with Rab1a and the Unc‐51‐like kinase 1 ( ULK 1) autophagy initiation complex. As a Rab1a effector, C9orf72 controls initiation of autophagy by regulating the Rab1a‐dependent trafficking of the ULK 1 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 C9 ALS / FTD patients. Finally, basal levels of autophagy were markedly reduced in C9 ALS / FTD patient‐derived iN eurons. 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 C9 ALS / FTD ‐associated p62 pathology.