title: Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling.
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.
authors.affiliation: 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.
authors.forename: Janet
authors.initials: J
authors.lastname: Ugolino
authors.affiliation: 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.
authors.forename: Yon Ju
authors.initials: YJ
authors.lastname: Ji
authors.affiliation: 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.
authors.forename: Karen
authors.initials: K
authors.lastname: Conchina
authors.affiliation: 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.
authors.forename: Justin
authors.initials: J
authors.lastname: Chu
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Raja Sekhar
authors.initials: RS
authors.lastname: Nirujogi
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Akhilesh
authors.identifier: http://orcid.org/0000-0001-9943-6127
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Maryland, United States of America.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Brady
authors.affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Maryland, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Hamacher-Brady
authors.affiliation: 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.
authors.forename: Jiou
authors.identifier: http://orcid.org/0000-0001-9115-8708
authors.initials: J
authors.lastname: Wang
mesh_terms: D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D000073885:C9orf72 Protein; D002352:Carrier Proteins / Q000235:genetics*; D042622:DNA Repeat Expansion / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D051379:Mice; D010641:Phenotype; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000073885:C9orf72 Protein; C000606498:C9orf72 protein, mouse; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; C000618232:SMCR8 protein, mouse; C484068:Tcfeb protein, mouse; C546843:mTOR protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases