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PLoS Genet. 2016 Nov 22;12(11):e1006443. doi: 10.1371/journal.pgen.1006443. eCollection 2016 Nov.

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

Author information

1
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, and Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
2
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
3
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Maryland, United States of America.

Abstract

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.

PMID:
27875531
PMCID:
PMC5119725
DOI:
10.1371/journal.pgen.1006443
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors have declared that no competing interests exist.

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