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Oligodendroglia metabolically support axons and contribute to neurodegeneration
Open accessAbstract
Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.
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“Remyelination is a crucial regenerative process in demyelinating diseases, limiting persisting damage to the CNS. It restores saltatory nerve conduction and ensures trophic support of axons.”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“It is finally in agreement with axonal degeneration observed in mice lacking the monocarboxylate transporter MCT1 in oligodendrocytes lineage cells (Lee et al., 2012;Philips et al., 2021).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Lee et al., 2012
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“This led to a working model of glycolytic oligodendrocytes providing direct metabolic support to axons via non-compacted cytoplasmic channels in myelin and monocarboxylate transporters, which preserves functional integrity and axon survival (Amaral et al., 2013;Fünfschilling et al., 2012;Lee et al., 2012).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Lee et al., 2012
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“As oligodendrocytes support axonal energy metabolism and neuronal health4–7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [6]
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“Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters.”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Lee et al., 2012
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“This opens the possibility that glycolytic oligodendrocytes, which are suggested to support electrically active axons with an excess of glycolysis products (Fünfschilling et al., 2012;Lee et al., 2012;Saab et al., 2016;Trevisiol et al., 2017) do so primarily by self-made pyruvate.”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Lee et al., 2012
In the citing paper
“an essential lactate transporter in the CNS whose expression is regulated by autophagy [458].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [458]
In the citing paper
“and lower levels of SLC16A1/MCT1 (solute carrier family 16 member 1), an essential lactate transporter in the CNS whose expression is regulated by autophagy [458].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [458]
In the citing paper
“blocking neuronal oxidative utilization of lactate affects neuronal survival and even memory formation (Suzuki et al., 2011; Lee et al., 2012).”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as Lee et al., 2012
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“This confirms that axons readily use lactate for ATP generation”
From Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism (2016) · cites this paper as Lee et al., 2012
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“After Breg transfer, the thickness of myelin around remyelinated axons increases, and OPCs and newly-generated OLs are recruited [182].”
BackgroundInfluentialPotential Roles of the WNT Signaling Pathway in Amyotrophic Lateral Sclerosis
Jiang, X., Guan, Y., Zhao, Z., Meng, F., Wang, X., Gao, X., Liu, J., Chen, Y., Zhou, F., Zhou, F., et al. (2021) · Cells · doi:10.3390/cells10040839 · Cited by 48
“Oligodendrocytes generate and maintain the myelin sheath insulating the axon [73] as well as providing neurons with metabolic support [74].”
BackgroundMonocarboxylate transporters: new players in body weight regulation
Carneiro, L., & Pellerin, L. (2015) · Obesity Reviews · doi:10.1111/obr.12256 · Cited by 45
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Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation
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“Myelin sheaths are essential for rapid propagation of action potentials but also provide metabolic and trophic factor support to stabilize and protect neuronal axons, thereby preventing axon degeneration (Funfschilling et al., 2012; Lee et al., 2012).”
BackgroundConverging Patterns of α-Synuclein Pathology in Multiple System Atrophy
Brettschneider, J., Suh, E. R., Robinson, J. L., Fang, L., Lee, E. B., Irwin, D. J., Grossman, M., Deerlin, V. M. V., Lee, V. M. ‐., & Trojanowski, J. Q. (2018) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nly080 · Cited by 45
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“In the CNS, oligodendrocytes provide metabolic support to the axon, most likely by exporting energy-rich metabolites via monocarboxylate transporters (Fünfschilling et al., 2012; Lee et al., 2012).”
N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation
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“In addition to speeding conduction of the action potential, myelination supports axon health and survival (3 – 5).”
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“The myelin sheath allows fast conduction velocity of electrical impulses along axons and provides metabolic support from the oligodendrocyte cell body to the underlying axon [34, 68].”
BackgroundAxo-Glia Interaction Preceding CNS Myelination Is Regulated by Bidirectional Eph-Ephrin Signaling
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“…of the oligodendroglial lactate transporter, MCT1, a protein with decreased expression in oligodendrocytes of affected ALS postmortem tissue, results in axon damage and loss of neuronal support underscoring the importance of oligodendroglial metabolic integrity to ALS pathology (Lee et al., 2012).”
BackgroundConcepts for regulation of axon integrity by enwrapping glia
Beirowski, B. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00256 · Cited by 47
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Interactions Between Astrocytes and Oligodendroglia in Myelin Development and Related Brain Diseases
Hu, X., Yu, G., Liao, X., & Xiao, L. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00981-z · Cited by 48
“It has been found that conditional knockout of MCT1 in OLs leads to myelin dysfunction and axonal degeneration [69], and impairment of MCT1-mediated lactate transport from OLs to axons is considered to contribute to the pathogenesis of amyotrophic lateral sclerosis [4].”
BackgroundKann, O. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15867 · Cited by 44
“…including action potential generation and propagation, can be fueled by lactate shuttled from myelinating oligodendrocytes and Schwann cells (Brown, Evans, et al., 2012; Fünfschilling et al., 2012; Lee et al., 2012; Philips & Rothstein, 2017; Saab et al., 2016; Stedehouder et al., 2017) (Figure 3).”
BackgroundCrosstalk of Signaling and Metabolism Mediated by the NAD+/NADH Redox State in Brain Cells
Winkler, U., & Hirrlinger, J. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1526-0 · Cited by 43
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“Mediating the response of oligodendroglia during injury is the primary focus of oligodendrocyte and myelinaffected diseases such as MS, ALS, Alzheimer’s and more.”
InfluentialAbdelkarim, D., Zhao, Y., Turner, M. P., Sivakolundu, D. K., Lu, H., & Bart Rypma, A. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.005 · Cited by 47
Neuronal lactate levels depend on glia‐derived lactate during high brain activity in Drosophila
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“…transport of monocarboxylates is relevant in vivo and which cells in the mammalian brain are responsible for their production and use is still a matter of intense debate and research (Baltan, 2015; Barros & Weber, 2018; Dienel, 2012; Funfschilling et al., 2012; Lee et al., 2012; Yellen, 2018).”
BackgroundExpedition into Exosome Biology: A Perspective of Progress from Discovery to Therapeutic Development
Jan, A. T., Rahman, S., Badierah, R., Lee, E. J., Mattar, E. H., Redwan, E. M. M. M., & Choi, I. (2021) · Cancers · doi:10.3390/cancers13051157 · Cited by 44
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BackgroundNeurodegeneration in Multiple Sclerosis: The Role of Nrf2-Dependent Pathways
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“In MS, the first autoimmune attack against myelin and OLs settles a chronic and escalating neuroinflammatory niche that fosters the activation of microglia, astrocytes, and perivascular macrophages [1].”
BackgroundMultiple Sclerosis and Aging: The Dynamics of Demyelination and Remyelination
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“MCT1 is highly enriched within oligodendroglia and a decrease of this transporter has been reported in patients with ALS and mouse models of ALS [155].”
BackgroundMyelin dysfunction in aging and brain disorders: mechanisms and therapeutic opportunities
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“The critical nature of this lactate shuttle was further supported 89 by the findings that genetic disruption of monocarboxylate transporter 1 in OLs leads to progressive axonal degeneration, even in the presence of intact myelin, firmly establishing that trophic metabolic support is separable from…”
Self-citation
Metadata
- Authors
- Lee, Y., Morrison, B. M., Li, Y., Lengacher, S., Farah, M. H., Hoffman, P. N., Liu, Y., Tsingalia, A., Jin, L., Zhang, P.-W., Pellerin, L., Magistretti, P. J., & Rothstein, J. D.
- Affiliations
- Johns Hopkins University (US)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Lausanne (CH)
- Corresponding author
- Rothstein, Jeffrey D.
- ORCID
- Venue
- Nature
- Published
- 2012-07
- Volume
- 487
- Issue
- 7408
- Pages
- 443-448
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3408792
- OpenAlex
- W2038811384
- Cited by
- 1,664
- References
- 49
- Citations by year
- 2026: 110 · 2025: 107 · 2024: 130 · 2023: 118 · 2022: 133 · 2021: 150 · 2020: 141 · 2019: 107 · 2018: 110 · 2017: 133 · 2016: 107 · 2015: 106 · 2014: 98 · 2013: 97 · 2012: 13
- FWCI
- 72.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation
- Muscular Dystrophy Association
- Johns Hopkins University
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A, 108336, 125063)
- Fonds De La Recherche Scientifique - FNRS
- National Institutes of Health
- National Institute on Aging (P50AG005146, P50AG05146)
- National Institute of Neurological Disorders and Stroke (P01NS016375, NS 33958, P01 NS16375, R01NS033958)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- oligodendroglia, MCT1, lactate transport, axonal degeneration, neurodegeneration, amyotrophic lateral sclerosis, oligodendrocytes, neuronal loss, lactate export
- MeSH terms
- Superoxide Dismutase-1, Monocarboxylate Transport Protein 1, Amyotrophic Lateral Sclerosis, Animals, Axons, Cell Line, Cell Survival, Disease Models, Animal, Heterozygote, Humans, Mice, Transgenic, Motor Neurons, Myelin Sheath, Nerve Degeneration, Oligodendroglia, Superoxide Dismutase, Down-Regulation, Lactic Acid, Protein Transport, Monocarboxylic Acid Transporters, Symporters, RNA, Small Interfering, Mice
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