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.

Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling

“…There have been recent reports describing C9orf72’s functions in autophagy [39, 41–43], including a decrease in autophagy initiation as a result of knockdown of C9orf72 [41, 42]. These observations are not necessarily mutually exclusive to our present study.…”

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

“…Although studies in mice have indicated that C9orf72 activity is important for myeloid cell function 14,18 , a report in mouse neurons and zebrafish suggests that C9orf72 isoform A may modulate poly-Q Ataxin-2 toxicity 20 , and studies have implicated C9ORF72 in regulating autophagy 20,31,32,38 , our study provides the first direct evidence showing that gain- and loss-of-function C9ORF72 mechanisms cooperate to cause the degeneration of human motor neurons. Recent studies have shown that C9ORF72 isoform A, but not isoform B, can form a functional complex with SMCR8 and WDR41 20 .…”

Loss of C9orf72 function leads to autoimmunity

“…Impairment of autophagy leads to accumulation of p62, a selective substrate of autophagy, which forms aggregates with ubiquitin (9). C9orf72 is a Rab1 effector that promotes initiation of autophagy, and disruption of C9orf72 function in cell lines and primary neurons inhibits autophagy and increased ER stress (10). This latter has been an expected finding since autophagy alleviates ER stress (11).…”

“…O'Rourke et al showed that C9orf72 is required for normal function of myeloid cells and microglia, since loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia (6). Also, C9orf72 depletion in HeLa cells and neurons caused accumulation of p62-positive inclusion, thus mimicking p62 pathology in ALS/FTD (10).…”