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Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling
Open accessAbstract
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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“Paradoxically, however, c9orf72 knockout in mouse (which models the loss of function attributed to the hexanucleotide repeat expansion) enhances autophagy by de-repressing MTOR and, in turn, increasing TFEB nuclear translocation [179,180].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [180]
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BackgroundSelf-citationBeckers, J., & Damme, P. V. (2025) · Autophagy Reports · doi:10.1080/27694127.2025.2474796 · Cited by 19
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“C9orf72 has also been proposed to play a role in autophagic flux [32,34,35], endosomal trafficking [36–38] and regulating AMPA receptor levels [39].”
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Solomon, D. A., Mitchell, J. C., Salcher-Konrad, M.-T., Vance, C. A., & Mizielinska, S. (2018) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12536 · Cited by 16
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“Most C9ORF72 knockdown [230] and knockout [231–237] in mice mainly develop an inflammatory phenotype, sometimes associated with a reduced lifespan, but no locomotor deficits or motor neuron degeneration.”
Houghton, O. H., Mizielinska, S., & Gómez‐Suaga, P. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.838402 · Cited by 12
“…function, vesicular trafficking, and cytoskeleton organization Autophagy initiation: (Amick et al., 2016; Sellier et al., 2016; Sullivan et al., 2016; Ugolino et al., 2016; Webster et al., 2016; Yang et al., 2016; Liu et al., 2018; Zhang et al., 2018; Cali et al., 2019; Ho et al., 2019; Ji et al.,…”
BackgroundInfluentialC9orf72 protein quality control by UBR5‐mediated heterotypic ubiquitin chains
Jülg, J., Edbauer, D., & Behrends, C. (2023) · EMBO Reports · doi:10.15252/embr.202255895 · Cited by 11
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“Loss - of - function of the C9orf72 gene, which encodes a guanine nucleotide exchange factor implicated in autophagy and immune responses, exacerbates gain - of - function toxicity (19–24).”
Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog
Langseth, A. J., Kim, J., Ugolino, J., Shah, Y., Hwang, H., Wang, J., Bergles, D. E., & Brown, S. P. (2017) · Scientific Reports · doi:10.1038/s41598-017-05864-2 · Cited by 13
Self-citationMultifaceted role of SMCR8 as autophagy regulator
Jung, J., & Behrends, C. (2017) · Small GTPases · doi:10.1080/21541248.2017.1346553 · Cited by 13
“In addition, overexpression or depletion of C9ORF72 increased or reduced SMCR8 protein levels, respectively and vice versa.(15,16,19) Finally, size exclusion chromatography determined co-migration of SMCR8 with C9ORF72 and WDR41 in a complex of about 600 kDa.”
BackgroundInfluentialHereditary Motor Neuropathies and Amyotrophic Lateral Sclerosis: a Molecular and Clinical Update
García-Santibáñez, R., Burford, M. J., & Bucelli, R. C. (2018) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-018-0901-z · Cited by 14
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Jiang, L., Zhang, T., Lu, K., & Qi, S. (2021) · Small GTPases · doi:10.1080/21541248.2021.1892443 · Cited by 13
“It was further confirmed that WDR41 is indispensable for recruiting C9orf72 and SMCR8 to lysosomes during starvation [148].”
BackgroundInfluentialC9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice
Lopez-Herdoiza, M.-B., Bauché, S., Wilmet, B., Duigou, C. L., Roussel, D., Frah, M., Béal, J., Devely, G., Boluda, S., Frick, P., et al. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1155929 · Cited by 13
“…involved in the autophagy/lysosomal functions, which are commonly altered in C9orf72 KO animals (Koppers et al., 2015; Atanasio et al., 2016; Burberry et al., 2016; Jiang et al., 2016; O’Rourke et al., 2016; Sudria-Lopez et al., 2016; Sullivan et al., 2016; Ugolino et al., 2016; Zhu et al., 2020).”
BackgroundResultInfluentialAberrant protein aggregation in amyotrophic lateral sclerosis
Wang, H., & Zeng, R. (2024) · Journal of Neurology · doi:10.1007/s00415-024-12485-z · Cited by 11
Mitochondrial Dysfunction in Repeat Expansion Diseases
Giménez-Bejarano, A., Alegre-Cortés, E., Yakhine-Diop, S. M. S., Gómez‐Suaga, P., & Fuentes, J. M. (2023) · Antioxidants · doi:10.3390/antiox12081593 · Cited by 12
Gagliardi, D., Costamagna, G., Taiana, M. M., Andreoli, L., Biella, F., Bersani, M., Bresolin, N., Comi, G. P., & Corti, S. P. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101172 · Cited by 11
“Consistent with this evidence, lack of C9orf72 and SMCR8 alters the expression of the autophagy markers LC3 and p62 (Sellier et al., 2016; Ugolino et al., 2016; Yang et al., 2015).”
BackgroundJin, W., Zhang, J., Chen, X., Yin, S., Yu, H., Gao, F., & Yao, D. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188916 · Cited by 10
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“Loss-of-function C9orf72 mutations disrupt the transcription factor EB (TFEB) signalling of autophagic induction, impair the interaction with autophagy GTPases, and inhibit autoly-sosome formation [112, 113].”
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“Interestingly, it has been shown that loss of C9orf72 strongly link to autophagic regulation 19,34,36 e 40 .”
Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs
Gilbert, J. W., Kennedy, Z., Godinho, B. M. D. C., Summers, A., Weiss, A., Echeverria, D., Bramato, B. M., McHugh, N., Cooper, D., Yamada, K., et al. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102291 · Cited by 8
Proteostasis deregulation as a driver of C9ORF72 pathogenesis
Torres, P., Cabral‐Miranda, F., Gonzalez‐Teuber, V., & Hetz, C. A. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15529 · Cited by 9
“Importantly, the C9ORF72- SMCR8 complex was also shown to influence the phosphorylative activity of the mammalian target of rapamycin complex 1 (mTORC1), the main player in nutrient sensing and autophagy regulation (Amick et al., 2016; Ugolino et al., 2016).”
BackgroundLin, L. T., Shenouda, M., McGoldrick, P., Lau, A., & Robertson, J. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02061-5 · Cited by 8
“C9orf72 has demonstrated roles in autophagy regulation, forming a complex with SMCR8 and WDR41 to promote autophagy initiation through ULK1 [14, 15] and to negatively regulate autophagy through an interaction with mTOR [16, 17].”
Leskelä, S., Huber, N., Hoffmann, D. B., Rostalski, H., Remes, A. M., Takalo, M., Hiltunen, M., & Haapasalo, A. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2021.119021 · Cited by 10
“different neuronal and non-neuronal [21,22,50,51].”
Autophagy in proteostasis and aging in Caenorhabditis elegans
Lange, C. M., Higuchi‐Sanabria, R., & Kumsta, C. (2025) · Cell Stress and Chaperones · doi:10.1016/j.cstres.2025.100115 · Cited by 11
“98 Thus, C9orf72 dysfunction can either impair or hyperactivate autophagy depending on species and cellular context.”
Veverová, K., Katonová, A., Horáková, H., Laczó, J., Angelucci, F., Hort, J., Lautrup, S., Fang, E. F., & Vyhnálek, M. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-01954-9 · Cited by 7
“Loss of these proteins led to decreased mTOR activity and increased nuclear translocation of TFEB, enhancing autophagy, lysosomal biogenesis, and lysosomal protein (LAMP1, LAMP2) expression [40, 43].”
Autophagy in motor neuron diseases
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“Other reports suggests that C9orf72 plays a role in mammalian Target of Rapamycin (mTOR) and Transcription Factor EB (TFEB) signaling [186, 187], in stress granule assembly [188], or in actin dynamics [189].”
BackgroundmiR-142-3p alleviates neuronal apoptosis in Parkinson’s disease via negatively regulating C9orf72
Meng, Q., Chen, J., Liang, Y., Zhang, X., Ding, J., Fang, Y., & Hu, G. (2024) · Neuroscience Letters · doi:10.1016/j.neulet.2024.137887 · Cited by 7
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Jaramillo, J., Solano, J. M., Aristizábal, A., & Garro, J. M. M. (2022) · Biomédica · doi:10.7705/biomedica.6060 · Cited by 3
“SOD1 encodes the enzyme superoxide dismutase 1, responsible for the degradation of superoxide ions via reactions with zinc and copper ions (1,7,11), while C9orf72 encodes a protein involved in both nuclear membrane transport and as a guanine nucleotide exchange factor that activates GTPases (5,12,13).”
BackgroundGu, Y., Wang, Y., Zhang, H., Zhao, T., Sun, S., Wang, H., Zhu, B., & Li, P. (2017) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b1600123 · Cited by 3
“Protein of transfected cells was extracted with Tris-HCl buffer following the published protocol (Ugolino et al., 2016), and 60 μg protein was subjected to electrophoresis with 12% (0.12 g/ml) sodium dodecyl sulfate (SDS)-polyacrylamide gel and transferred to a nylon membrane.”
InfluentialC9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle
Sironi, F. M., Parlanti, P., Margotta, C., Cassarà, J., Bonetto, V., Bendotti, C., Tortarolo, M., & Cappello, V. (2025) · Cells · doi:10.3390/cells14221765 · Cited by 2
“C9orf72 is known to regulate mitochondrial function by interacting with the prohibitin complex, which controls cristae morphogenesis and mitochondrial integrity [29].”
InfluentialPAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis
Singh, J., Lescouzères, L., Zaouter, C., Chaineau, M., Haghi, G., Durcan, T. M., & Patten, S. A. (2026) · Brain · doi:10.1093/brain/awag092 · Cited by 2
“115 Given that mTORC1 signalling is a master driver of de novo purine synthesis 116-118 and promotes the spatial assembly of the ‘purino-some’, 119 which is a multi-enzyme complex required for efficient purine production, its suppression in C9orf72 -LOF conditions might lead to diminished PAICS…”
Autophagy–exosome crosstalk in neurodegeneration: Mechanisms and therapeutic opportunities
Sedighi, S., Guan, T., Michetti, F., Cordani, M., Behrooz, A. B., Sabouni, F., Eshraghi, M., Saleem, A., Ghavami, S., & Aghanoori, M. (2026) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2026.109025 · Cited by 3
m6A Methylation‐Induced Autophagy Impairment by TFEB Regulation in SOD1 ‐ G93A ALS Cell Model
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“Loss of C9orf72 suppresses mTOR signaling, upregulates TFEB activity, and enhances autophagic flux, but this may lead to systemic imbalance (Ugolino et al. 2016).”
Neurodegenerative Diseases and Autophagy
Fleming, A., Vicinanza, M., Renna, M., Puri, C., Ricketts, T., Füllgrabe, J., López, A., de Jager, S. M., Ashkenazi, A., Tanasa, M. P., et al. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-811304-2.00011-0 · Cited by 2
“It has been recently reported that loss of C9ORF72 induces autophagy via mTOR and TFEB signaling (Ugolino et al., 2016).”
BackgroundRounding, N. (2018) · White Rose eTheses Online (University of Leeds, The University of Sheffield, University of York) · Cited by 2
Infante-Tadeo, S., & Barber, D. L. (2025) · Molecular Biology of the Cell · doi:10.1091/mbc.e24-12-0539 · Cited by 2
“Our findings are in agreement with previous reports indicating that loss of C9orf72 function in HEK293T cells leads to nuclear translocation of TFEB (Ugolino et al., 2016; Wang et al., 2020).”
Lysosomal dysfunction in neurodegenerative disease
Brooker, S. M., Coukos, R., & Krainc, D. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-026-01262-3 · Cited by 1
“Reduced mTORC1 signalling in C9orf72-deficient cells, in turn, is associated with upregulation of TFEB, a master regulator of lysosomal biogenesis and autophagosome formation 298,299 .”
Alzheimer’s Disease and Frontotemporal Lobar Degeneration: Mouse Models
Ittner, L. M., Lee, W. S., Stefanoska, K., Asih, P. R., & Ke, Y. D. (2018) · Springer eBooks · doi:10.1007/978-3-319-72938-1_10 · Cited by 1
Differential response of C9orf72 transcripts following neuronal depolarization
Ghaffari, L., Trotti, D., & Haeusler, A. R. (2023) · iScience · doi:10.1016/j.isci.2023.106959 · Cited by 1
“We did not detect the rapid changes in protein levels of C9orf72 by western blotting as observed with the transcripts, which could be in part because of protein turnover rates for this protein, which are estimated to be 6–9 h in HEK293T cells.(54) Overall, these results show that, in rat cortical neurons, C9orf72 is d…”
BackgroundFlight to insight: maximizing the potential of Drosophila models of C9orf72-FTD
d’Almeida, N. A., & Tipping, M. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1434443 · Cited by 1
“…(Liu et al., 2018), WDR41, SMCR8, Rab proteins, and the ULK1 complex involved in autophagy initiation (Sellier et al., 2016; Sullivan et al., 2016; Webster et al., 2016; Yang et al., 2016), and a master regulator of metabolism, mTOR (Amick et al., 2016; Ugolino et al., 2016; Ji et al., 2017).”
BackgroundThe Misfolding Pathway of SOD1: Implications for Drug Design in ALS
Ip, P. (2017) · TSpace (University of Toronto)
New understanding of TFEB and autophagy in the development of endometriosis：reviewPreprint
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Structural basis for the ARF GAP activity and specificity of the C9orf72 complexPreprint
Su, M.-Y., Fromm, S. A., Remis, J. P., Toso, D. B., & Hurley, J. H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.13.439632
The Microbiome of ALS – Does It Start from the Gut?
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Effect of G 4 C 2 Repeat Expansions on the Motion of Lysosomes Inside NeuritesPreprint
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The Motor Neuron Diseases and Amyotrophic Lateral Sclerosis
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Metadata
- Authors
- Ugolino, J., Ji, Y. J., Conchina, K., Chu, J., Nirujogi, R. S., Pandey, A., Brady, N. R., Hamacher-Brady, A., & Wang, J.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Wang, Jiou
- Venue
- PLOS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-11-22
- Volume
- 12
- Issue
- 11
- Pages
- e1006443
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC5119725
- OpenAlex
- W2555959842
- Cited by
- 185
- References
- 60
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 16 · 2023: 15 · 2022: 11 · 2021: 29 · 2020: 37 · 2019: 22 · 2018: 22 · 2017: 18
- FWCI
- 19.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health (NS074324, NS089616)
- The Robert Packard Center for ALS Research at Johns Hopkins
- National Cancer Institute (5T32CA009110)
- Maryland Technology Development Corporation (15075235)
- U.S. Department of Defense (US) (W81XWH-15-1-0069)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- C9orf72, SMCR8, autophagy, mTOR signaling, TFEB, S6K1 phosphorylation, nutrient sensing, amyotrophic lateral sclerosis, frontotemporal dementia, hexanucleotide repeat expansion, lysosomal function, protein complexes, metabolic regulation
- MeSH terms
- C9orf72 Protein, Alleles, Amyotrophic Lateral Sclerosis, Animals, Autophagy, Carrier Proteins, Gene Expression Regulation, Humans, Phenotype, Signal Transduction, Guanine Nucleotide Exchange Factors, Ribosomal Protein S6 Kinases, 90-kDa, DNA Repeat Expansion, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Frontotemporal Dementia, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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