Cited by 481Amyotrophic Lateral Sclerosis ResearchCellular transport and secretionAutophagy in Disease and Therapy

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C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking

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Farg, Manal A., Sundaramoorthy, Vinod, Sultana, Jessica M., Yang, Shu, Atkinson, Rachel A.K., Levina, Vita, Halloran, Mark A., Gleeson, Paul A., Blair, Ian P., Soo, Kai Y., King, Anna E., Atkin, Julie D.·2014·Human Molecular Genetics

DOI 10.1093/hmg/ddu068PMC PMC5886132

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Abstract

Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However, the cellular function of the C9ORF72 protein remains unknown. Here, we demonstrate that C9ORF72 regulates endosomal trafficking. C9ORF72 colocalized with Rab proteins implicated in autophagy and endocytic transport: Rab1, Rab5, Rab7 and Rab11 in neuronal cell lines, primary cortical neurons and human spinal cord motor neurons, consistent with previous predictions that C9ORF72 bears Rab guanine exchange factor activity. Consistent with this notion, C9ORF72 was present in the extracellular space and as cytoplasmic vesicles. Depletion of C9ORF72 using siRNA inhibited transport of Shiga toxin from the plasma membrane to Golgi apparatus, internalization of TrkB receptor and altered the ratio of autophagosome marker light chain 3 (LC3) II:LC3I, indicating that C9ORF72 regulates endocytosis and autophagy. C9ORF72 also colocalized with ubiquilin-2 and LC3-positive vesicles, and co-migrated with lysosome-stained vesicles in neuronal cell lines, providing further evidence that C9ORF72 regulates autophagy. Investigation of proteins interacting with C9ORF72 using mass spectrometry identified other proteins implicated in ALS; ubiquilin-2 and heterogeneous nuclear ribonucleoproteins, hnRNPA2/B1 and hnRNPA1, and actin. Treatment of cells overexpressing C9ORF72 with proteasome inhibitors induced the formation of stress granules positive for hnRNPA1 and hnRNPA2/B1. Immunohistochemistry of C9ORF72 ALS patient motor neurons revealed increased colocalization between C9ORF72 and Rab7 and Rab11 compared with controls, suggesting possible dysregulation of trafficking in patients bearing the C9ORF72 repeat expansion. Hence, this study identifies a role for C9ORF72 in Rab-mediated cellular trafficking.

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BackgroundSelf-citation
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TMEM106B and ApoE polymorphisms in CHMP2B-mediated frontotemporal dementia (FTD-3)
Rostgaard, N., Roos, P., Budtz–Jørgensen, E., Johannsen, P., Waldemar, G., Nørremølle, A., Lindquist, S. G., Gydesen, S., Brown, J. M., Collinge, J., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.06.026 · Cited by 6
“In this context it is intr guing that accumulating evidence points to a role for C9orf72 in endolysosomal trafficking and autophagy (Busch et al., 2016; Farg et al., 2014; Levine et al., 2013; Sellier et al., 2016; Zhang et al., 2012).”
Neurodegenerative Disease Conditions and Genomic Treatment for Better Health
Badhe, R. V., Chejara, D. R., Kumar, P., Choonara, Y. E., & Pillay, V. (2018) · Springer eBooks · doi:10.1007/978-981-10-7506-3_15 · Cited by 6
Effect of Mutations in SOD1 and C9orf72 Genes on Autophagy in Lymphomonocytes in Myotrophic Lateral Sclerosis
Kochergin, I. A., Shpilyukova, Y. A., Лысогорская, Е. В., Abramycheva, N. Y., Zakharova, M. N., & Illarioshkin, S. N. (2019) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-019-04595-w · Cited by 6
Molecular interactions between C9ORF72 and SMCR8: A local energetic frustration perspective
Kumar, V. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.07.016 · Cited by 6
Autophagy-Lysosome Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration
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Cellular and molecular phenotypes of C9orf72 ALS/FTD patient derived iPSC-microglia mono-culturesPreprint
Lorenzini, I., Alsop, E. B., Levy, J., Gittings, L. M., Lall, D., Rabichow, B. E., Moore, S. R., Pevey, R. S., Bustos, L. M., Burciu, C., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.09.03.277459 · Cited by 6
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“Furthermore, chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of ALS, is a GEF for Rab8 and is also associated with Rab1 [18, 19].”
Background
Apolipoprotein L1 is increased in frontotemporal lobar degeneration post-mortem brain but not in ante-mortem cerebrospinal fluid
Hok‐A‐Hin, Y. S., Dijkstra, A. A., Rábano, A., Hoozemans, J. J. M., Castillo, L. O., Seelaar, H., Swieten, J. C. V., Pijnenburg, Y. A. L., Teunissen, C. E., & del Campo, M. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105813 · Cited by 5
Propranolol reduces the accumulation of cytotoxic aggregates in C9orf72-ALS/FTD in vitro models
Seidel, M., Rajkumar, S., Steffke, C., Noeth, V., Agarwal, S., Roger, K., Lipecka, J., Ludolph, A. C., Guerrera, I. C., Boeckers, T. M., et al. (2023) · Current Research in Neurobiology · doi:10.1016/j.crneur.2023.100105 · Cited by 5
Pathogenesis underlying hexanucleotide repeat expansions in C9orf72 gene in amyotrophic lateral sclerosis
Chong, Z. Z., Menkes, D. L., & Souayah, N. (2023) · Reviews in the Neurosciences · doi:10.1515/revneuro-2023-0060 · Cited by 6
Indacaterol inhibits collective cell migration and IGDQ-mediated single cell migration in metastatic breast cancer MDA-MB-231 cells
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“Moreover, ATXN2 was found to colocalize with Rab11 and Rab4 [26], which are proteins involved respectively in integrin α5β1 and αvβ3 recycling [27] (Fig.”
Background
Comprehensive mapping of mutations in the C9ORF72 that affect folding and binding to SMCR8 protein
Xue, B., Li, R., Ma, H., Rahaman, A., & Kumar, V. (2022) · Process Biochemistry · doi:10.1016/j.procbio.2022.07.013 · Cited by 5
Huntingtin and Other Neurodegeneration-Associated Proteins in the Development of Intracellular Pathologies: Potential Target Search for Therapeutic Intervention
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Genetics of Frontotemporal Dementia
Heetveld, S., Rizzu, P., & Heutink, P. (2015) · Springer eBooks · doi:10.1007/978-3-319-17223-1_5 · Cited by 5
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The Lysosome in Aging‐Related Neurodegenerative Diseases
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Analysis of C9orf72 repeat length in progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, and atypical parkinsonism
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Cognitive Decline in Parkinsonism: From Clinical Phenotypes to the Genetic Background
Koros, C., Stanitsa, E., Angelopoulou, E., Papageorgiou, S. G., & Stefanis, L. (2025) · Biomedicines · doi:10.3390/biomedicines13071624 · Cited by 5
“C9orf72 protein is thought to play a key role in the regulation of endosomal trafficking [113], RNA processing [114], and nucleocytoplasmic transport [115].”
Innate immune sensing of macromolecule homeostasis
Yang, K., Jeltema, D., & Yan, N. (2024) · Advances in immunology · doi:10.1016/bs.ai.2024.03.004 · Cited by 4
Overexpression of Toxic Poly(Glycine-Alanine) Aggregates in Primary Neuronal Cultures Induces Time-Dependent Autophagic and Synaptic Alterations but Subtle Activity Impairments
Steffke, C., Agarwal, S., Kabashi, E., & Catanese, A. (2024) · Cells · doi:10.3390/cells13151300 · Cited by 4
Development of LNA Gapmer Oligonucleotide-Based Therapy for ALS/FTD Caused by the C9orf72 Repeat Expansion
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Genetics of familial amyotrophic lateral sclerosis
Savinova, A. V., Shnayder, N. A., & Nasyrova, R. F. (2021) · Bulletin of Siberian Medicine · doi:10.20538/1682-0363-2021-3-193-202 · Cited by 4
“Recent studies indicate that this gene participates in the regulation of vesicular transport [83].”
Background
Hexanucleotide repeat expansions in C9orf72 alter microglial responses and prevent a coordinated glial reaction in ALSPreprint
Masrori, P., Bijnens, B., Davie, K., Poovathingal, S. K., Storm, A., Hersmus, N., Fumagalli, L., Bosch, L. V. D., Fiers, M. W. E. J., Thal, D. R., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.26.513909 · Cited by 4
PU.1 restores microglial dysfunction caused by C9ORF72 repeat expansions in neural organoids
Ljubikj, T., Mars, M., van der Geest, A. T., Jakobs, C. E., Bessler, N., Donega, V., van den Oetelaar, X. P. R. M., de Wit, M., & Pasterkamp, R. J. (2025) · Brain · doi:10.1093/brain/awaf340 · Cited by 4
Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers
Hnath, B., Ekambaram, S., & Dokholyan, N. V. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2026.107309 · Cited by 3
Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases
Balak, C. D., Schlachetzki, J. C. M., Lana, A. J., West, E., Hong, C., DuGal, J., Zhou, Y., Li, B., Spann, N. J., Saisan, P. A., et al. (2026) · Immunity · doi:10.1016/j.immuni.2026.07.008 · Cited by 7
Targets and Gene Therapy of ALS (Part 1)
Shiryaeva, O. A., Tolochko, C., Alekseeva, T. M., & Dyachuk, V. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26094063 · Cited by 4
“In ALS patients with the C9orf72 mutation, an increase has been observed in the number of cells with C9orf72 colocalization with Rab7 or Rab11 compared to the control group, which indicates the disruption of endosomal transport regulation in ALS patients [10].”
Spinal Cord Phosphoproteome of SCA2 Mouse Model Reveals Alteration of ATXN2-N-Term PRM–SH3–Actin Interactome and of Autophagy
Almaguer-Mederos, L. E., Kandi, A. R., Şen, N.-E., Canet-Pons, J., Berger, L.-M., Stokes, M. P., Abell, K., Key, J., Gispert, S., & Auburger, G. W. J. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.101072 · Cited by 5
“…of UBQLN2, with its ability to access phase-separated RNP complexes and to degrade rER proteins via the proteasome or via lysosomes (220), with an ALS phenotype upon mutation (221, 222), appeared to relate to the RNA-binding features of ATXN2 and to its preferential impact on motor neurons.”
Endocytosis
Basturea, G. N. (2019) · Materials and Methods · doi:10.13070/mm.en.9.2752 · Cited by 3
The prion-like effect and prion-like protein targeting strategy in amyotrophic lateral sclerosis
Wenzhi, Y., Xiangyi, L., & Dongsheng, F. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e34963 · Cited by 3
“Experiments in vitro and in vivo showed knockout of C9orf72 resulted in reduction of endocytic transport and exosome secretion, which may lead to accumulation of DPRs [76,77].”
Background
Research progress on vesicular trafficking in amyotrophic lateral sclerosis
Chaosen, Y. A. N. G., & Zhang, X. (2022) · Journal of Zhejiang University (Medical Sciences) · doi:10.3724/zdxbyxb-2022-0024 · Cited by 3
Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cells and Brain Samples
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Authors: Farg, M. A., Sundaramoorthy, V., Sultana, J. M., Yang, S., Atkinson, R. A. K., Levina, V., Halloran, M. A., Gleeson, P. A., Blair, I. P., Soo, K. Y., King, A. E., & Atkin, J. D.
Affiliations: Macquarie University (AU)
University of Tasmania (AU)
La Trobe University (AU)
The University of Melbourne (AU)
Corresponding author: Atkin, Julie D.
ORCID: Sundaramoorthy, Vinod
Yang, Shu
Atkinson, Rachel A.K.
Levina, Vita
Halloran, Mark A.
Gleeson, Paul A.
Blair, Ian P.
King, Anna E.
Atkin, Julie D.
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2014-02-18
Volume: 23
Issue: 13
Pages: 3579-3595
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddu068
PMC: PMC5886132
OpenAlex: W2102327538
Cited by: 478
References: 66
Citations by year: 2026: 8 · 2025: 22 · 2024: 25 · 2023: 35 · 2022: 24 · 2021: 58 · 2020: 52 · 2019: 39 · 2018: 39 · 2017: 50 · 2016: 57 · 2015: 50 · 2014: 19
FWCI: 38.23
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
Locations: Human Molecular Genetics (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
eCite Digital Repository (University of Tasmania) (submittedVersion, cc-by-nc)
Own your potential (DEAKIN) (submittedVersion)
Figshare (submittedVersion, cc-by-nc)
Funders: Motor Neurone Disease Research Institute of Australia
La Trobe University
University of Wollongong
Medical Research Council
National Health and Medical Research Council (1004670, 1030513, 1006141)
Topics: Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords: C9orf72, amyotrophic lateral sclerosis, frontotemporal dementia, hexanucleotide repeat expansion, endosomal trafficking, Rab GTPases, autophagy, endocytosis, UBQLN2, hnRNP A1, HNRNPA2B1, stress granules, motor neurons, lysosomes, LC3, proteasome
MeSH terms: Autophagy-Related Proteins, C9orf72 Protein, rab7 GTP-Binding Proteins, rab11 GTP-Binding Proteins, Amyotrophic Lateral Sclerosis, Animals, Biological Transport, Humans, Proteins, Endosomes, Mass Spectrometry, rab GTP-Binding Proteins, Adaptor Proteins, Vesicular Transport, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Adaptor Proteins, Signal Transducing, Mice, Frontotemporal Dementia

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C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking

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