ArticlePLoS genetics2016
Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling.
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 117 papers, 1 of them a synthesis that pooled it.
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Who cites it
117 citing papers in PubMed, 1 synthesis or guideline pooled it, 187 citations in OpenAlex.
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis.Brain : a journal of neurology · 2026Article
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.The EMBO journal · 2026Article
- Patient-derived induced pluripotent stem cells with a C9orf72 expansion as a model to study frontotemporal dementia pathologies.Molecular biology of the cell · 2025Article
- Article
- C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.Acta neuropathologica communications · 2025Article
- Distinctive autophagy/mitophagy biomarker profiles in frontotemporal lobar degeneration and Alzheimer's disease.Acta neuropathologica communications · 2025Article
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS/FTD.Molecular neurobiology · 2024Article
- Identification of selective and non-selectiveMolecular therapy. Nucleic acids · 2024Article
- Brain-body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis.Nature reviews. Neurology · 2024Review
- Aberrant protein aggregation in amyotrophic lateral sclerosis.Journal of neurology · 2024Review
- Zfp106 binds to G-quadruplex RNAs and inhibits RAN translation and formation of RNA foci caused by G4C2 repeats.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction.Acta pharmaceutica Sinica. B · 2024Article
- Molecular hallmarks of ageing in amyotrophic lateral sclerosis.Cellular and molecular life sciences : CMLS · 2024Review
- Myeloid and lymphoid expression ofScience translational medicine · 2024Article
- Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.Cells · 2024Review
- Flight to insight: maximizing the potential ofFrontiers in molecular neuroscience · 2024Article
- Pathomechanistic Networks of Motor System Injury in Amyotrophic Lateral Sclerosis.Current neuropharmacology · 2024Review
57 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.