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C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking
Open accessAbstract
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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“Interestingly, the impaired endocytic signaling has been observed during C9ORF72 mutated conditions in C9ORF72 ALS/FTD patients as well as the SH-SY5Y cell line model, suggesting that the expression of C9ORF72 modulates endocytosis [172,173].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [172]
Experimental — accuracy not yet measuredIn the citing paper
“The C9orf72 protein belongs to the DENN (differentially expressed in normal and neoplastic cells) family [143,144] and binds the GTPases RAB7 and RAB11, which are involved in endosome maturation and recycling [145].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [145]
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“Mutations in Rab7 cause Charcot-Marie-Tooth disease type 2B (38), and Rab7-positive endosome abnormalities impair trafficking in Wobbler mice (39).”
BackgroundDynein Dysfunction Induces Endocytic Pathology Accompanied by an Increase in Rab GTPases
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“Defects in protein degradation are increasingly implicated in ALS pathogenesis (19) and mutations in ubiquilin-2 (20), which regulates autophagy and the UPS by binding/transport of protein cargo (21), also cause ALS/FTD.”
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Low Dose Proteasome Inhibition Affects Alternative Splicing
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“Inhibition of the proteasome in cells overexpressing C9ORF72 induces the formation of SGs We next transfected neuro2a cells with a construct-encoding C9ORF72 tagged with GFP.”
BackgroundInfluentialFTD/ALS families are no longer orphaned
Swieten, J. C. V., & Grossman, M. (2012) · Neurology · doi:10.1212/wnl.0b013e318268471a · Cited by 5
Flagged first, then by citations
Research works printed but not linked: 1
- Arancibia-Carcamo, 2006, Chapter 6. Frontiers in Neuroscience
Cited by
Sorted by citations
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894
Self-citationGuidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1
Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,897
Self-citationAutophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities
Menzies, F. M., Fleming, A., Caricasole, A., Bento, C. F., Andrews, S. P., Ashkenazi, A., Füllgrabe, J., Jackson, A., Jimenez Sanchez, M., Karabiyik, C., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.01.022 · Cited by 1,134
“A role has been suggested for C9ORF72 in endocytic vesicle trafficking and autophagy (Farg et al., 2014).”
Bang, J., Spina, S., & Miller, B. L. (2015) · The Lancet · doi:10.1016/s0140-6736(15)00461-4 · Cited by 1,144
Compromised autophagy and neurodegenerative diseases
Menzies, F. M., Fleming, A., & Rubinsztein, D. C. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3961 · Cited by 851
Metadata
- 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
- 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
- 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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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.
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