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Oligodendroglia metabolically support axons and contribute to neurodegeneration

Nature volume 487, pages 443–448 (2012)Cite this article

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Abstract

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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Figure 1: MCT1 expressed primarily within oligodendroglia in the CNS.
Figure 2: MCT1 required for neuronal survival in vitro.
Figure 3: Lentiviral MCT1 shRNA is toxic to motoneurons.
Figure 4: Heterozygous MCT1 -null mice develop widespread axonopathy.
Figure 5: Selective downregulation of MCT1 in oligodendroglia produces axonal injury.
Figure 6: MCT1 reduced in ALS patients and SOD1(G93A) mice.

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Acknowledgements

We thank C. Coccia, S. Vidensky, I. Shats, L. Chakravarti, Y. Ayukawa and L. Mamedova for technical support, E. Potter for oligodendrocyte cultures, C. Cooke for electron microscopy, and S. Kang and D. Bergles for providing MOBP–eGFP BAC and CNP BacTrap mice, CASPR and Nav1.6 antibodies. Autopsy specimens were provided by the Johns Hopkins ALS Tissue Bank and the Johns Hopkins University Brain Resource Center supported by National Institutes of Health grants P50AG05146 and PO1NS16375. Support was provided by the Muscular Dystrophy Association (B.M.M. and Yo.L.), NIH-NS33958 (J.D.R.), P2ALS (J.D.R.), Packard Center for ALS (J.D.R.), Human Frontier Science Program-RG118/1998-B (L.P.), Swiss Fonds National de Recherche Scientifique-31003A-125063 (L.P.), Swiss National Science Foundation (FNRS)-3100AO-108336/1 (P.J.M.), Biaggi and Puccini Foundations (P.J.M). We dedicate this manuscript to J. W. Griffin, who passed away while this manuscript was under revision, and are grateful for his contributions to this manuscript and mentorship to many of the authors on this paper.

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Author notes

  1. Youngjin Lee and Brett M. Morrison: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, The Johns Hopkins University, 855 North Wolfe Street, Rangos 248, Baltimore, Maryland 21205, USA,

    Youngjin Lee, Brett M. Morrison, Yun Li, Mohamed H. Farah, Paul N. Hoffman, Yiting Liu, Akivaga Tsingalia, Lin Jin, Ping-Wu Zhang & Jeffrey D. Rothstein

  2. School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne (EPFL), Station 19, CH-1015 Lausanne, Switzerland,

    Sylvain Lengacher & Pierre J. Magistretti

  3. Department of Physiology, University of Lausanne, 7 Rue du Bugnon, CH-1005 Lausanne, Switzerland,

    Luc Pellerin

  4. Department of Neuroscience, The Johns Hopkins University, 855 North Wolfe Street, Rangos 270, Baltimore, Maryland 21205, USA,

    Jeffrey D. Rothstein

  5. The Brain Science Institute, The Johns Hopkins University, 855 North Wolfe Street, Rangos 270, Baltimore, Maryland 21205, USA,

    Jeffrey D. Rothstein

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Contributions

All of the authors contributed to the design of the experiments. MCT1 BAC reporter experiments were designed and performed by Yo.L., L.J. and P.-W.Z. MCT1 ASO, MCT1i and human western blot experiments were designed and performed by B.M.M., Yu.L., A.T., Yi.L. and J.D.R. Lentiviral experiments were designed and performed by Yo.L., B.M.M., Yu.L. and J.D.R. The heterozygous MCT1-null mice were produced by S.L., L.P. and P.J.M., and analysed by Yo.L. Electron miscroscopy work was completed by M.H.F., Yo.L., B.M.M. and J.D.R. Optic nerve lentiviral injections were performed by P.N.H. The manuscript and figures were prepared by B.M.M. and J.D.R. with input from co-authors.

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Correspondence to Jeffrey D. Rothstein.

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Lee, Y., Morrison, B., Li, Y. et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443–448 (2012). https://doi.org/10.1038/nature11314

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