The C9orf72 protein interacts with Rab1a and the ULK 1 complex to regulate initiation of autophagy

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. image C9 ALS / FTD ‐associated C9orf72 is a Rab1a effector that controls initiation of autophagy by regulating ULK 1 complex trafficking. Disruption of C9orf72 function inhibits autophagy and mimics the p62 pathology found in C9 ALS / FTD patients. C9 ALS / FTD iN eurons display reduced autophagy. C9orf72 regulates ULK 1 complex‐dependent initiation of autophagy. C9orf72 is a Rab1a effector that controls trafficking of the ULK 1 complex. C9orf72 deficiency inhibits autophagy and mimics C9 ALS / FTD p62 pathology. C9 ALS / FTD patient‐derived iN eurons display reduced autophagy.