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.
| Original language | English (US) |
|---|---|
| Article number | e1006443 |
| Journal | PLoS genetics |
| Volume | 12 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2016 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research
Cite this
Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling. / Ugolino, Janet; Ji, Yon Ju; Conchina, Karen; Chu, Justin; Nirujogi, Raja Sekhar; Pandey, Akhilesh; Brady, Nathan R.; Hamacher-Brady, Anne; Wang, Jiou.
In: PLoS genetics, Vol. 12, No. 11, e1006443, 01.11.2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling
AU - Ugolino, Janet
AU - Ji, Yon Ju
AU - Conchina, Karen
AU - Chu, Justin
AU - Nirujogi, Raja Sekhar
AU - Pandey, Akhilesh
AU - Brady, Nathan R.
AU - Hamacher-Brady, Anne
AU - Wang, Jiou
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85000866292&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85000866292&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1006443
DO - 10.1371/journal.pgen.1006443
M3 - Article
C2 - 27875531
AN - SCOPUS:85000866292
VL - 12
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 11
M1 - e1006443
ER -