Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons
Open accessAbstract
An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD.
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PIKFYVE inhibition improves proteostasis in neurons.
“improves proteostasis in neurons (Shi et al., 2018; Staats et al., 2019).”
From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Shi et al., 2018
In “Small molecule and genetic regulators of endosomal trafficking rescue patient iMN survival” (page unavailable), the paper reports that PIKFYVE inhibition lowers glutamate-receptor levels and improves survival in C9ORF72 patient motor neurons. It proposes that increased autophagosome–lysosome fusion may help remove dipeptide repeat proteins, but does not establish a general improvement in neuronal proteostasis. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPIKFYVE inhibition increases the number of EEA1-positive endosomes and LAMP1-positive lysosomes.
“PIKFYVE inhibition increases the number of EEA1-positive endosomes and LAMP1-positive lysosomes”
From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Shi et al., 2018
The section on small-molecule regulators of endosomal trafficking (page not provided) reports that PIKFYVE inhibition increased the size of EEA1-positive endosomes, not their number. The lysosomal-biogenesis section attributes restored numbers of LAMP1-positive lysosomes to forced C9ORF72 expression; our copy does not report that PIKFYVE inhibition increased their number. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe human iPSC line WTC11 was used in isogenic GRN+/+ and GRN−/− forms.
“Isogenic human iPSC line WTC11 (GRN+/+ and GRN−/−) were generated by Dr. Bruce R. Conklin, as previously described (61).”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [61]
The Methods sections on iPSC reprogramming and CRISPR/Cas9 genome editing describe patient-derived iPSCs and C9ORF72-edited cells, respectively. Searches for WTC11, GRN isogenic lines, and Bruce R. Conklin found no passage in our copy identifying the claimed GRN+/+ and GRN−/− WTC11 lines or their origin. (LLM, conf=0.78)
Experimental — accuracy not yet measuredInduced expression of different transcription factors yields other neuron types, such as motor neurons and inhibitory neurons.
“induced expression of different transcription factors yield other types of neurons, such as motor neurons (Hester et al., 2011; Shi et al., 2018) and inhibitory neurons (Yang et al., 2017).”
From CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons (2019) · cites this paper as Shi et al., 2018
C9orf72 assists in the formation of nascent autophagosomes, consistent with impaired autophagy observed in murine cortical neurons and human iPSC-derived neurons upon C9orf72 knockdown.
“Together, these findings suggest that C9orf72 assists in the formation of nascent autophagosomes, consistent with the finding of impaired autophagy in murine cortical neurons [148] and human iPSC-derived neurons [154] upon C9orf72 knockdown.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [154]
Loss of C9orf72 function and consequent impairment in autophagy may enhance DPR accumulation in C9orf72 mutation carriers, acting synergistically to accentuate neurodegeneration.
“Furthermore, the loss of C9orf72 function and consequent impairment in autophagy may enhance DPR accumulation in C9orf72 mutation carriers, acting synergistically to accentuate neurodegeneration [154,172,173].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [154]
Neurons derived from iPSCs carrying the C9orf72 repeat expansion recapitulate key features of cellular pathology associated with ALS, including hyperexcitability and decreased viability upon exposure to excitotoxic agents such as glutamate.
“Further, neurons derived from iPSCs carrying the C9orf72 repeat expansion recapitulate key features of cellular pathology associated with ALS, including hyperexcitability [154,188,189] and decreased viability upon exposure to excitotoxic agents such as glutamate [154,190,191].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [154]
Components of the cortico-spinal-motor pathway have been generated or studied in isolation, but the in vitro derivation and assembly of this three-part system with human cells had not been achieved.
“Although components of the cortico-spinal-motor pathway have been generated or studied in isolation (Ogura et al., 2018; Sances et al., 2016; Shi et al., 2018; Steinbeck et al., 2016), the in vitro derivation and assembly of this three-part system have not yet been achieved with human cells.”
From Generation of Functional Human 3D Cortico-Motor Assembloids (2020) · cites this paper as Shi et al., 2018
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- [32]Webster CP, The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J 35, 1656– 1676 (2016). 27334615 PMC4969571
- [39]Sellier C, Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J 35, 1276– 1297 (2016). 27103069 PMC4910533
Cited by
Sorted by citations
C9orf72-mediated ALS and FTD: multiple pathways to disease
Balendra, R., & Isaacs, A. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0047-2 · Cited by 715 · see citing works
CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons
Tian, R., Gachechiladze, M. A., Ludwig, C. H., Laurie, M. T., Hong, J. Y., Nathaniel, D., Prabhu, A. V., Fernandopulle, M. S., Patel, R., Abshari, M., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.07.014 · Cited by 543 · see citing works
Self-citationGeneration of Functional Human 3D Cortico-Motor Assembloids
Andersen, J., Revah, O., Miura, Y., Thom, N., Amin, N. D., Kelley, K. W., Singh, M., Chen, X., Thete, M. V., Walczak, E. M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.11.017 · Cited by 593 · see citing works
Animal models of neurodegenerative diseases
Dawson, T. M., Golde, T. E., & Lagier-Tourenne, C. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0236-8 · Cited by 576 · see citing works
Transcription factor-mediated differentiation of human iPSCs into neurons
Fernandopulle, M. S., Prestil, R., Grunseich, C., Wang, C., Gan, L., & Ward, M. E. (2018) · Current Protocols in Cell Biology · doi:10.1002/cpcb.51 · Cited by 461 · see citing works
Self-citationALS Genetics: Gains, Losses, and Implications for Future Therapies
Kim, G., Gautier, O., Tassoni-Tsuchida, E., Ma, X. R., & Gitler, A. D. (2020) · Neuron · doi:10.1016/j.neuron.2020.08.022 · Cited by 370 · see citing works
Molecular mechanisms underlying nucleotide repeat expansion disorders
Malik, I., Kelley, C. P., Wang, E. T., & Todd, P. K. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00382-6 · Cited by 363 · see citing works
C9orf72 suppresses systemic and neural inflammation induced by gut bacteria
Burberry, A., Wells, M. F., Limone, F., Couto, A., Smith, K. S., Keaney, J., Gillet, G., van Gastel, N., Wang, J.-Y., Pietilainen, O., et al. (2020) · Nature · doi:10.1038/s41586-020-2288-7 · Cited by 314 · see citing works
The overlapping genetics of amyotrophic lateral sclerosis and frontotemporal dementia
Abramzon, Y. A., Fratta, P., Traynor, B. J., & Chia, R. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00042 · Cited by 244 · see citing works
Amyotrophic lateral sclerosis: translating genetic discoveries into therapies
Akçimen, F., Lopez, E. R., Landers, J. E., Nath, A., Chiò, A., Chia, R., & Traynor, B. J. (2023) · Nature Reviews Genetics · doi:10.1038/s41576-023-00592-y · Cited by 234 · see citing works
Zhu, Q., Jiang, J., Gendron, T. F., McAlonis-Downes, M., Jiang, L., Taylor, A., Diaz Garcia, S., Ghosh Dastidar, S., Rodriguez, M. J., King, P., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0619-5 · Cited by 220 · see citing works
Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
“gy in murine cortical neurons [148] and human iPSC-derived neurons [154] upon C9orf72 knockdown.”
BackgroundBowles, K. R., Silva, M. C., Whitney, K., Bertucci, T., Berlind, J. E., Lai, J. D., Garza, J. C., Boles, N. C., Mahali, S., Strang, K. H., et al. (2021) · Cell · doi:10.1016/j.cell.2021.07.003 · Cited by 175 · see citing works
Self-citationLaflamme, C., McKeever, P. M., Kumar, R., Schwartz, J., Kolahdouzan, M., Chen, C. X., You, Z., Benaliouad, F., Gileadi, O., McBride, H. M., et al. (2019) · eLife · doi:10.7554/elife.48363 · Cited by 155 · see citing works
Review: neuropathology of non-tau frontotemporal lobar degeneration
Neumann, M., & Mackenzie, I. R. A. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12526 · Cited by 144 · see citing works
Boivin, M., Pfister, V., Gaucherot, A., Ruffenach, F., Negroni, L., Sellier, C., & Charlet‐Berguerand, N. (2020) · The EMBO Journal · doi:10.15252/embj.2018100574 · Cited by 137 · see citing works
Bassil, R., Shields, K., Granger, K., Zein, I., Ng, S., & Chih, B. (2021) · Nature Communications · doi:10.1038/s41467-021-25344-6 · Cited by 106 · see citing works
Modeling cell-autonomous motor neuron phenotypes in ALS using iPSCs
Hawrot, J., Imhof, S., & Wainger, B. J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104680 · Cited by 74 · see citing works
Ho, R., Workman, M. J., Mathkar, P., Wu, K., Kim, K. J., O’Rourke, J. G., Kellogg, M., Montel, V., Banuelos, M. G., Arogundade, O. A., et al. (2021) · Cell Systems · doi:10.1016/j.cels.2020.10.010 · Cited by 62 · see citing works
Eitan, C., Siany, A., Barkan, E., Olender, T., van Eijk, K. R., Moisse, M., Farhan, S. M. K., Danino, Y. M., Yanowski, E., Marmor-Kollet, H., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01040-6 · Cited by 38 · see citing works
Self-citationWDR41 supports lysosomal response to changes in amino acid availability
Amick, J., Tharkeshwar, A. K., Amaya, & Ferguson, S. M. (2018) · Molecular Biology of the Cell · doi:10.1091/mbc.e17-12-0703 · Cited by 39 · see citing works
Approaches to gene modulation therapy for ALS
Meijboom, K. E., & Brown, R. H. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01285-w · Cited by 38 · see citing works
Chai, N., Haney, M. S., Couthouis, J., Morgens, D. W., Benjamin, A., Wu, K., Ousey, J., Fang, S., Finer, S., Bassik, M. C., et al. (2020) · Brain Research · doi:10.1016/j.brainres.2019.146601 · Cited by 26 · see citing works
Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS
Bekier, M. E., Pinarbasi, E., Krishnan, G., Mesojedec, J. J., Hurley, M., Harikumar Sheela, H., Collins, C. A., Ghaffari, L., de Majo, M., Ullian, E. M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188138 · Cited by 2 · see citing works
“For iNeuron differentiation, iPSCs were transduced with NGN2-express-ing lentivirus constructs, and a previously published protocol was followed for differentiation (61).”
- Authors
- Shi, Y., Lin, S., Staats, K. A., Li, Y., Chang, W.-H., Hung, S.-T., Hendricks, E., Linares, G. R., Wang, Y., Son, E. Y., Wen, X., Kisler, K., Wilkinson, B., Menendez, L., Sugawara, T., Woolwine, P., Huang, M., Cowan, M. J., Ge, B., Koutsodendris, N., Sandor, K. P., Komberg, J., Vangoor, V. R., Senthilkumar, K., Hennes, V., Seah, C., Nelson, A. R., Cheng, T.-Y., Lee, S.-J. J., August, P. R., Chen, J. A., Wisniewski, N., Hanson-Smith, V., Belgard, T. G., Zhang, A., Coba, M., Grunseich, C., Ward, M. E., van den Berg, L. H., Pasterkamp, R. J., Trotti, D., Zlokovic, B. V., & Ichida, J. K.
- Affiliations
- University of Southern California (US)
- Stanford Medicine (US)
- Thomas Jefferson University (US)
- University Medical Center Utrecht (NL)
- DRVision Technologies (United States) (US)
- Verge Genomics (United States) (US)
- National Institutes of Health (US)
- Corresponding author
- Ichida, Justin K
- ORCID
- Staats, Kim A
- Li, Yichen
- Chang, Wen-Hsuan
- Hung, Shu-Ting
- Linares, Gabriel R
- Wang, Yaoming
- Son, Esther Y
- Wen, Xinmei
- Kisler, Kassandra
- Wilkinson, Brent
- Menendez, Louise
- Ge, Brandon
- Koutsodendris, Nicole
- Vangoor, Vamshidhar R
- Seah, Carina
- Nelson, Amy R
- August, Paul R
- Chen, Jason A
- Hanson-Smith, Victor
- Belgard, T Grant
- Zhang, Alice
- Coba, Marcelo
- Ward, Michael E
- Pasterkamp, R Jeroen
- Trotti, Davide
- Zlokovic, Berislav V
- Ichida, Justin K
- Venue
- Nature Medicine
- Published
- 2018-02-05
- Volume
- 24
- Issue
- 3
- Pages
- 313-325
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6112156
- OpenAlex
- W2787234767
- Cited by
- 566
- References
- 66
- Citations by year
- 2026: 23 · 2025: 59 · 2024: 63 · 2023: 73 · 2022: 64 · 2021: 86 · 2020: 83 · 2019: 68 · 2018: 47
- FWCI
- 48.22
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- National Institute on Aging (R01AG023084, R01AG039452, R37AG023084, P50AG005142, RF1AG039452, P01AG052350)
- National Institute on Deafness and Other Communication Disorders (R01DC015530, T32DC009975)
- National Institute of Neurological Disorders and Stroke (R21NS090912, R00NS077435, R37NS034467, R01NS097850, K99NS077435, R01NS034467)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- C9orf72, GGGGCC repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, haploinsufficiency, motor neurons, neurodegeneration, vesicle trafficking, lysosomal biogenesis, endosomes, glutamate receptors, excitotoxicity, dipeptide repeat proteins, Rab5, ALS2, FIG4, CHMP2B, optineurin, p62
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Gene Expression Regulation, Humans, Introns, Motor Neurons, Mutation, Nerve Degeneration, Endosomes, rab5 GTP-Binding Proteins, DNA Repeat Expansion, Frontotemporal Dementia, Haploinsufficiency
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.
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