Systemic deregulation of autophagy upon loss of ALS- and FTD-linked C9orf72.
A genetic mutation in the C9orf72 gene causes the most common forms of neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 protein, predicted to be a DENN-family protein, is reduced in ALS and FTD, but its functions remain poorly understood. Using a 3110043O21Rik/C9orf72 knockout mouse model, as well as cellular analysis, we have found that loss of C9orf72 causes alterations in the signaling states of central autophagy regulators. In particular, C9orf72 depletion leads to reduced activity of MTOR, a negative regulator of macroautophagy/autophagy, and concomitantly increased TFEB levels and nuclear translocation. Consistent with these alterations, cells exhibit enlarged lysosomal compartments and enhanced autophagic flux. Loss of the C9orf72 interaction partner SMCR8 results in similar phenotypes. Our findings suggest that C9orf72 functions as a potent negative regulator of autophagy, with a central role in coupling the cellular metabolic state with autophagy regulation. We thus propose C9orf72 as a fundamental component of autophagy signaling with implications in basic cell physiology and pathophysiology, including neurodegeneration.
a Department of Biochemistry and Molecular Biology , Bloomberg School of Public Health, Johns Hopkins University , Baltimore , MD USA.|b Department of Neuroscience , School of Medicine, Johns Hopkins University , Baltimore , MD USA.
Yon Ju
YJ
Ji
a Department of Biochemistry and Molecular Biology , Bloomberg School of Public Health, Johns Hopkins University , Baltimore , MD USA.|b Department of Neuroscience , School of Medicine, Johns Hopkins University , Baltimore , MD USA.
Janet
J
Ugolino
c Department of Molecular Microbiology and Immunology , Bloomberg School of Public Health, Johns Hopkins University , Baltimore , MD USA.
Nathan Ryan
NR
Brady
a Department of Biochemistry and Molecular Biology , Bloomberg School of Public Health, Johns Hopkins University , Baltimore , MD USA.|c Department of Molecular Microbiology and Immunology , Bloomberg School of Public Health, Johns Hopkins University , Baltimore , MD USA.
Anne
A
Hamacher-Brady
a Department of Biochemistry and Molecular Biology , Bloomberg School of Public Health, Johns Hopkins University , Baltimore , MD USA.|b Department of Neuroscience , School of Medicine, Johns Hopkins University , Baltimore , MD USA.
Jiou
http://orcid.org/0000-0001-9115-8708
J
Wang
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D000073885:C9orf72 Protein / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D057180:Frontotemporal Dementia / Q000235:genetics; D018345:Mice, Knockout; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000073885:C9orf72 Protein; C000606498:C9orf72 protein, mouse; D002352:Carrier Proteins; C000618232:SMCR8 protein, mouse; C484068:Tcfeb protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
ALS; C9orf72; FTD; MTOR; SMCR8; TFEB; autophagy; lysosome; neurodegeneration; p62