Oligodendrocyte pathology exceeds axonal pathology in white matter in human amyotrophic lateral sclerosis
Open accessAbstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. The majority of cases are sporadic (sALS), while the most common inherited form is due to C9orf72 mutation (C9ALS). A high burden of inclusion pathology is seen in glia (including oligodendrocytes) in ALS, especially in C9ALS. Myelin basic protein (MBP) messenger RNA (mRNA) must be transported to oligodendrocyte processes for myelination, a possible vulnerability for normal function. TDP43 is found in pathological inclusions in ALS and is a component of mRNA transport granules. Thus, TDP43 aggregation could lead to MBP loss. Additionally, the hexanucleotide expansion of mutant C9ALS binds hnRNPA2/B1, a protein essential for mRNA transport, causing potential further impairment of hnRNPA2/B1 function, and thus myelination. Using immunohistochemistry for p62 and TDP43 in human post‐mortem tissue, we found a high burden of glial inclusions in the prefrontal cortex, precentral gyrus, and spinal cord in ALS, which was greater in C9ALS than in sALS cases. Double staining demonstrated that the majority of these inclusions were in oligodendrocytes. Using immunoblotting, we demonstrated reduced MBP protein levels relative to PLP (a myelin component that relies on protein not mRNA transport) and neurofilament protein (an axonal marker) in the spinal cord. This MBP loss was disproportionate to the level of PLP and axonal loss, suggesting that impaired mRNA transport may be partly responsible. Finally, we show that in C9ALS cases, the level of oligodendroglial inclusions correlates inversely with levels of hnRNPA2/B1 and the number of oligodendrocyte precursor cells. We conclude that there is considerable oligodendrocyte pathology in ALS, which at least partially reflects impairment of mRNA transport. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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SQSTM1-positive inclusions are found in the majority of patients with ALS and FTD and often overlap with inclusions that stain for ubiquitin and TARDBP/TDP-43.
“Furthermore, SQSTM1-positive inclusions are found in the majority of patients with ALS and FTD, and often overlap with inclusions that stain for ubiquitin and TARDBP/TDP-43 (TAR DNA binding protein), an essential RNA-binding protein integrally connected with ALS-FTD [82,116–118] (Figure 1).”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [82]
Individuals with disease-associated C9orf72 mutations display a significantly greater burden of SQSTM1-positive glial inclusions than those with sporadic ALS.
“In fact, individuals with disease-associated C9orf72 mutations display a significantly greater burden of SQSTM1-positive glial inclusions than those with sporadic ALS [82].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [82]
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TDP-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model
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“ALS/FTD patients carrying C9orf72 hexanucleotide expansion exhibit ubiquitin and p62 aggregation in cortical neurons, glial cells and skeletal muscle cells that appears to be more severe than sporadic ALS (Al-Sarraj et al., 2011; Lorente Pons et al., 2020; Troakes et al., 2012; Türk et al., 2014).”
BackgroundAcosta-Galeana, I., Hernandez-Martinez, R., Reyes-Cruz, T., Chiquete, E., & Buendia, J. D. J. A. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1193636 · Cited by 10 · see citing works
“These results, backed up by multiple other articles, highlight non-neuronal cells as a possible target not only for the treatment of ALS but for the expansion of basic knowledge of pathology (Philips et al., 2013; Pons et al., 2020; Heo et al., 2022).”
BackgroundResultBagheri, H., Friedman, H., Siminovitch, K., & Peterson, A. (2020) · bioRxiv · doi:10.1371/journal.pgen.1008752 · Cited by 9 · see citing works
Perić, M., Nikolic, L. M., Anđjus, P. R., & Bataveljić, D. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15451 · Cited by 10 · see citing works
“The initial indication of oligodendrocyte involvement in the ALS pathology was the identification of the protein aggregations in these cells in several CNS regions affected in ALS (Lorente Pons et al., 2020; Philips et al., 2013; Stieber et al., 2000).”
BackgroundDecoding the Cellular Trafficking of Prion-like Proteins in Neurodegenerative Diseases
Hu, C., Yan, Y., Jin, Y., Yang, J. H., Xi, Y., & Zhong, Z. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01115-9 · Cited by 11 · see citing works
Valori, C. F., & Neumann, M. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.724891 · Cited by 9 · see citing works
Myelin loss in C9orf72 hexanucleotide expansion carriers
Sirisi, S., Querol‐Vilaseca, M., Dols‐Icardo, O., Pegueroles, J., Montal, V., Muñoz, L., Torres, S., Ferrer‐Raventós, P., Iulita, M. F., Sánchez‐Aced, É., et al. (2022) · Journal of Neuroscience Research · doi:10.1002/jnr.25100 · Cited by 9 · see citing works
Barton, S. K., Gregory, J. M., Selvaraj, B. T., McDade, K., Henstridge, C. M., Spires‐Jones, T. L., James, O. G., Mehta, A. R., Story, D., Burr, K., et al. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.705306 · Cited by 8 · see citing works
Hughes, L. S., Fröhlich, A., Pfaff, A. L., Bubb, V. J., Quinn, J. P., & Kõks, S. (2024) · Biomolecules · doi:10.3390/biom14030358 · Cited by 8 · see citing works
“Figure S3: Boxplots of cis -acting SVA RIPs displaying three hits for the greatest effect size on gene upregulation.”
BackgroundWhat Is the Role of Oligodendrocytes in Amyotrophic Lateral Sclerosis?
Benarroch, E. E. (2021) · Neurology · doi:10.1212/wnl.0000000000012706 · Cited by 8 · see citing works
“The presence of TDP-43 aggregates in oligodendrocytes results in impaired MBP translation, myelin abnormalities, and axonal damage in patients with ALS carrying C9orf72 mutations.(19) Accumulation of cytoplasmic mutated FUS aggregates inmature oligodendrocytes also results in oligodendrocyte dysfunction and downregula…”
BackgroundRoles of Ion Channels in Oligodendrocyte Precursor Cells: From Physiology to Pathology
Wang, J., Shen, Y., Liao, P. S., Yang, B., & Jiang, R. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157336 · Cited by 6 · see citing works
“Dysfunction of non-neuronal cells, particularly oligodendrocytes in the CNS, has been increasingly implicated in driving disease progression [128,129].”
Mouhi, S., Pio, T., & Andersen, J. (2025) · Trends in Cell Biology · doi:10.1016/j.tcb.2025.11.003 · Cited by 7 · see citing works
Xia, T., Yang, C., Wang, X., Bai, L., Ma, J., Zhao, M., Hua, W., & Wang, H. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1034041 · Cited by 5 · see citing works
Ramya, V. J., Sarkar, N., Bhagat, S. K., Pradhan, R. K., Varghese, A. M., Nalini, A., Sathyaprabha, T. N., Raju, T. R., & Vijayalakshmi, K. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03375-y · Cited by 5 · see citing works
Wen, D., Li, Q., Li, Y., Yan, W., Wang, Y., & Liu, Y. (2025) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2025.07.011 · Cited by 5 · see citing works
“…LC3-interacting region (LIR) domain (Qiu et al., 2022). p62 has also been used to estimate autophagic flux, and p62 levels are inversely correlated with autophagic efficiency (Chua et al., 2022). p62-positive inclusions are found in the majority of ALS and FTD patients (Lorente Pons et al., 2020).”
Fukatsu, S., Sashi, H., Shirai, R., Takagi, N., Oizumi, H., Yamamoto, M., Ohbuchi, K., Miyamoto, Y., & Yamauchi, J. (2024) · Pathophysiology · doi:10.3390/pathophysiology31010008 · Cited by 4 · see citing works
“It is likely that FTDALS diseases including FTDALS1 affect not only neuronal cells but also oligodendroglial cells [51–55].”
BackgroundNeuroglia in neurodegeneration: Amyotrophic lateral sclerosis and frontotemporal dementia
Marchi, F. D., Spinelli, E. G., & Bendotti, C. (2025) · Handbook of clinical neurology · doi:10.1016/b978-0-443-19102-2.00004-1 · Cited by 3 · see citing works
Swindell, W. R. (2025) · NeuroSci · doi:10.3390/neurosci6030065 · Cited by 3 · see citing works
Oligodendroglia in Ageing and Age-Dependent Neurodegenerative Diseases
Niu, J., Verkhratsky, A., Butt, A. M., & Yi, C. (2025) · Advances in neurobiology · doi:10.1007/978-3-031-87919-7_13 · Cited by 3 · see citing works
Non-cell autonomous autophagy in amyotrophic lateral sclerosis: A new promising target?
Rosso, F., Magdalena, R., Torazza, C., Bacchetti, F., Milanese, M., Poletti, A., Bonanno, G., Cristofani, R., & Bonifacino, T. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107203 · Cited by 3 · see citing works
“This makes OLs and myelinated axons metabolically connected.”
InfluentialChang, J., Lipscombe, H., Lv, J., Mccombe, P., Henderson, R. D., Ngo, S., Steyn, F., & Shaw, T. B. (2026) · BMC Medicine · doi:10.1186/s12916-026-04763-6 · Cited by 2 · see citing works
JP1 peptide modulates oxidative stress and autophagy via Keap1-Nrf2-ARE in ALS model mice
Zhang, Y., Liu, Y., Shi, S., Li, Q., Huo, Y., You, P., Shu, M., Cheng, X., Zhang, J., Liang, D., et al. (2026) · BMC Medicine · doi:10.1186/s12916-026-05119-w · Cited by 1 · see citing works
Shandilya, A., & Mehan, S. (2021) · Research Square · doi:10.21203/rs.3.rs-721622/v1 · Cited by 1 · see citing works
Georgopoulou, M., Hobin, F., Dubin, J., Masrori, P., Arekatla, G., Poesen, K., Cruz, S. D., Bosch, L. V. D., Thal, D. R., Sifrim, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.09.693234 · Cited by 1 · see citing works
Role of Glial Cells in Neurodegenerative Diseases and Metals-Induced Neurotoxicity
Pajarillo, E. A. B., Nyarko‐Danquah, I., Digman, A., Kim, S., Ajayi, I., Aschner, M., & Lee, E. (2025) · Elsevier eBooks · doi:10.1016/b978-0-323-95488-4.00227-8
Neuroimaging in hereditary neuromuscular disorders: a literature review and clinical case reports
Bostanova, F., Валентиновна, Ш. И., & Murtazina, A. F. (2025) · Neuromuscular Diseases · doi:10.17650/2222-8721-2025-15-3-47-63
A Cross Talk Between Natural Biomolecules and Neuroglia
Iman, T., Akram, R., Tehreem, A., Asghar, A., Mustafa, M., & Iqbal, J. (2026) · IGI Global eBooks · doi:10.4018/979-8-3373-4139-2.ch001
cGAS inhibition delays TDP-43-driven ALS PathogenesisPreprint
Liu, Y., Feng, W., Aikedan, A., Lee, S.-I., Bhagwat, M., Nagiri, R. K., Wong, M. Y., Amin, S., Qu, W., Zhu, J., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.24.707791
“Disruption of oligodendrocyte lineage maturation and myelin integrity is a well-recognized feature of ALS pathology 38,39 .”
Vézina, A., Paquet, A., Blais, M., Gros‐Louis, F., Picher‐Martel, V., & Dupré, N. (2026) · Contemporary clinical neuroscience · doi:10.1007/978-3-032-18296-8_20
Granger, S. M., Staniforth, R. A., Snorradóttir, Á. Ó., Cooper‐Knock, J., Vos, K. J. D., & Highley, J. R. (2026) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.70083
Self-citationTDP-43 dysfunction destabilizes glial homeostatic identity in ALS/FTD
Dale, A. E., & Sattler, R. (2026) · Brain Research · doi:10.1016/j.brainres.2026.150618
- Authors
- Lorente Pons, A., Higginbottom, A., Cooper‐Knock, J., Alrafiah, A., Alofi, E., Kirby, J., Shaw, P. J., Wood, J. D., & Highley, J. R.
- Affiliations
- Sheffield Institute for Translational Neuroscience, University of Sheffield Sheffield UK
- University of Sheffield (GB)
- King Abdulaziz University (SA)
- Corresponding author
- Highley, J Robin
- ORCID
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2020-06-08
- Volume
- 251
- Issue
- 3
- Pages
- 262-271
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- OpenAlex
- W3021148913
- Cited by
- 57
- References
- 38
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 14 · 2020: 4
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Pathology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Funders
- “la Caixa” Foundation
- Pathological Society of Great Britain and Ireland
- Medical Research Council Canada
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- amyotrophic lateral sclerosis, C9orf72 mutation, white matter, myelin basic protein, mRNA transport, TDP-43, HNRNPA2B1, oligodendroglial inclusions, oligodendrocyte precursor cells, axonal pathology, neurofilaments, spinal cord, prefrontal cortex
- MeSH terms
- Sequestosome-1 Protein, C9orf72 Protein, Amyotrophic Lateral Sclerosis, Autopsy, Axons, DNA-Binding Proteins, Myelin Basic Protein, Humans, Mutation, Oligodendroglia, Phenotype, Pyramidal Tracts, RNA, Messenger, Transcription Factors, Biomarkers, Case-Control Studies, Genetic Predisposition to Disease, RNA Transport, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, White Matter
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