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

The most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia is a hexanucleotide repeat expansion in c9orf72. here we report a study of the c9orf72 protein by examining the consequences of loss of c9orf72 functions. deletion of one or both alleles of the c9orf72 gene in mice causes age-dependent lethality phenotypes. we demonstrate that c9orf72 regulates nutrient sensing as the loss of c9orf72 decreases phosphorylation of the mtor substrate s6k1. the transcription factor eb (tfeb),a master regulator of lysosomal and autophagy genes,which is negatively regulated by mtor,is substantially up-regulated in c9orf72 loss-of-function animal and cellular models. consistent with reduced mtor activity and increased tfeb levels,loss of c9orf72 enhances autophagic flux,suggesting that c9orf72 is a negative regulator of autophagy. we identified a protein complex consisting of c9orf72 and smcr8,both of which are homologous to denn-like proteins. the depletion of c9orf72 or smcr8 leads to significant down-regulation of each other’s protein level. loss of smcr8 alters mtor signaling and autophagy. these results demonstrate that the c9orf72-smcr8 protein complex functions in the regulation of metabolism and provide evidence that loss of c9orf72 function may contribute to the pathogenesis of relevant diseases. © 2016 ugolino et al.