|Title||The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Webster, CP, Smith, EF, Bauer, CS, Moller, A, Hautbergue, GM, Ferraiuolo, L, Myszczynska, MA, Higginbottom, A, Walsh, MJ, Whitworth, AJ, Kaspar, BK, Meyer, K, Shaw, PJ, Grierson, AJ, De Vos, KJ|
|Date Published||2016 Aug 1|
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.
|Alternate Journal||EMBO J.|
|PubMed Central ID||PMC4969571|