Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

Nature Neuroscience volume 16, pages 571–579 (2013)Cite this article

Subjects

Abstract

Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of amyotrophic lateral sclerosis (ALS) mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2+ cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. We found extensive degeneration of gray matter oligodendrocytes in the spinal cord of SOD1 (G93A) ALS mice prior to disease onset. Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in NG2+ cells were observed in motor cortex and spinal cord of ALS patients. Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Enhanced proliferation of NG2+ cells in the spinal cord of presymptomatic ALS mice.
Figure 2: Enhanced oligodendrogenesis in the spinal cord gray matter of adult ALS mice.
Figure 3: Progressive degeneration of oligodendrocytes in the spinal cord ventral gray matter of ALS mice.
Figure 4: Apoptosis of oligodendrocytes in the spinal cord of ALS mice.
Figure 5: Early disruption of oligodendrocyte structure in the spinal cord of ALS mice.
Figure 6: Myelin abnormalities and impaired maturation of adult-born oligodendrocytes in the spinal cord of ALS mice.
Figure 7: Demyelination in gray matter regions of the motor cortex and spinal cord in human ALS.
Figure 8: Excision of mutant SOD1 (G37R) from NG2+ cells delays disease onset and prolongs survival in ALS mice.

References

  1. Clement, A.M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113–117 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Boillée, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Yamanaka, K. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 11, 251–253 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ilieva, H., Polymenidou, M. & Cleveland, D.W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761–772 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kang, S.H., Fukaya, M., Yang, J.K., Rothstein, J.D. & Bergles, D.E. NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68, 668–681 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Magnus, T. et al. Adult glial precursor proliferation in mutant SOD1G93A mice. Glia 56, 200–208 (2008).

    Article  PubMed  Google Scholar 

  7. Nave, K.A. Myelination and support of axonal integrity by glia. Nature 468, 244–252 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Nave, K.A. & Trapp, B.D. Axon-glial signaling and the glial support of axon function. Annu. Rev. Neurosci. 31, 535–561 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Lee, Y. et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443–448 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Suzuki, A. et al. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144, 810–823 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rinholm, J.E. et al. Regulation of oligodendrocyte development and myelination by glucose and lactate. J. Neurosci. 31, 538–548 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Niebroj-Dobosz, I., Rafalowska, J., Fidzianska, A., Gadamski, R. & Grieb, P. Myelin composition of spinal cord in a model of amyotrophic lateral sclerosis (ALS) in SOD1G93A transgenic rats. Folia Neuropathol. 45, 236–241 (2007).

    CAS  PubMed  Google Scholar 

  13. Cosottini, M. et al. Magnetization transfer imaging demonstrates a distributed pattern of microstructural changes of the cerebral cortex in amyotrophic lateral sclerosis. AJNR Am. J. Neuroradiol. 32, 704–708 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rivers, L.E. et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat. Neurosci. 11, 1392–1401 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Zhu, X. et al. Age-dependent fate and lineage restriction of single NG2 cells. Development 138, 745–753 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gurney, M.E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Dal Canto, M.C. & Gurney, M.E. Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu,Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). Brain Res. 676, 25–40 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Woodruff, R.H., Tekki-Kessaris, N., Stiles, C.D., Rowitch, D.H. & Richardson, W.D. Oligodendrocyte development in the spinal cord and telencephalon: common themes and new perspectives. Int. J. Dev. Neurosci. 19, 379–385 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Guo, F. et al. Pyramidal neurons are generated from oligodendroglial progenitor cells in adult piriform cortex. J. Neurosci. 30, 12036–12049 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Jamin, N., Junier, M.P., Grannec, G. & Cadusseau, J. Two temporal stages of oligodendroglial response to excitotoxic lesion in the gray matter of the adult rat brain. Exp. Neurol. 172, 17–28 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Wu, Y.J., Tang, Y.F., Xiao, Z.C., Bao, Z.M. & He, B.P. NG2 cells response to axonal alteration in the spinal cord white matter in mice with genetic disruption of neurofilament light subunit expression. Mol. Neurodegener. 3, 18 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Coutts, M., Kong, L.X. & Keirstead, H.S. A model of motor neuron loss: selective deficits after ricin injection. J. Neurotrauma 27, 1333–1342 (2010).

    Article  PubMed  Google Scholar 

  24. Henson, P.M., Bratton, D.L. & Fadok, V.A. Apoptotic cell removal. Curr. Biol. 11, R795–R805 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Locatelli, G. et al. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nat. Neurosci. 15, 543–550 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Pohl, H.B. et al. Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage. J. Neurosci. 31, 1069–1080 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Woodruff, R.H., Fruttiger, M., Richardson, W.D. & Franklin, R.J. Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination. Mol. Cell Neurosci. 25, 252–262 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Chang, A., Nishiyama, A., Peterson, J., Prineas, J. & Trapp, B.D. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J. Neurosci. 20, 6404–6412 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pouly, S., Becher, B., Blain, M. & Antel, J.P. Expression of a homologue of rat NG2 on human microglia. Glia 27, 259–268 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Bu, J., Akhtar, N. & Nishiyama, A. Transient expression of the NG2 proteoglycan by a subpopulation of activated macrophages in an excitotoxic hippocampal lesion. Glia 34, 296–310 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Higuchi, M. et al. Axonal degeneration induced by targeted expression of mutant human tau in oligodendrocytes of transgenic mice that model glial tauopathies. J. Neurosci. 25, 9434–9443 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yazawa, I. et al. Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45, 847–859 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Horner, P.J., Thallmair, M. & Gage, F.H. Defining the NG2-expressing cell of the adult CNS. J. Neurocytol. 31, 469–480 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Fünfschilling, U. et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485, 517–521 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Bruijn, L.I. et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18, 327–338 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Pramatarova, A., Laganiere, J., Roussel, J., Brisebois, K. & Rouleau, G.A. Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J. Neurosci. 21, 3369–3374 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rothstein, J.D., Van Kammen, M., Levey, A.I., Martin, L.J. & Kuncl, R.W. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol. 38, 73–84 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Nagai, M. et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat. Neurosci. 10, 615–622 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gong, Y.H., Parsadanian, A.S., Andreeva, A., Snider, W.D. & Elliott, J.L. Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis, but does not cause motoneuron degeneration. J. Neurosci. 20, 660–665 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yamanaka, K. et al. Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc. Natl. Acad. Sci. USA 105, 7594–7599 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Aebischer, J. et al. Elevated levels of IFNgamma and LIGHT in the spinal cord of patients with sporadic amyotrophic lateral sclerosis. Eur. J. Neurol. 19, 752–759 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Buntinx, M. et al. Cytokine-induced cell death in human oligodendroglial cell lines. I. Synergistic effects of IFN-gamma and TNF-alpha on apoptosis. J. Neurosci. Res. 76, 834–845 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Neumann, M. et al. TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions. J. Neuropathol. Exp. Neurol. 66, 177–183 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Tu, P.H. et al. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann. Neurol. 44, 415–422 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Komori, T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Brain Pathol. 9, 663–679 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Bauer, J. et al. Endoplasmic reticulum stress in PLP-overexpressing transgenic rats: gray matter oligodendrocytes are more vulnerable than white matter oligodendrocytes. J. Neuropathol. Exp. Neurol. 61, 12–22 (2002).

    Article  PubMed  Google Scholar 

  47. Chong, S.Y. et al. Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination. Proc. Natl. Acad. Sci. USA 109, 1299–1304 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Dutta, R. & Trapp, B.D. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 68, S22–S31 (2007).

    Article  PubMed  Google Scholar 

  49. Rudick, R.A. & Trapp, B.D. Gray-matter injury in multiple sclerosis. N. Engl. J. Med. 361, 1505–1506 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Doerflinger, N.H., Macklin, W.B. & Popko, B. Inducible site-specific recombination in myelinating cells. Genesis 35, 63–72 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Novak, A., Guo, C., Yang, W., Nagy, A. & Lobe, C.G. Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis 28, 147–155 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Muzumdar, M.D., Tasic, B., Miyamichi, K., Li, L. & Luo, L. A global double-fluorescent Cre reporter mouse. Genesis 45, 593–605 (2007).

    CAS  PubMed  Google Scholar 

  54. Gong, S. et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank N. Ye, I. Srivastava, S. Singh and T. Le for their excellent technical support, M. Pucak for help with Imaris software operation and quantitative analysis, J. Carmen for her contributions to the Cre/lox animal study, and H. Zhang at the Johns Hopkins University School of Public Health FACS core for assistance with NG2+ cell isolation. We thank B. Trapp (Cleveland Clinic Lerner Research Institute) for advice regarding human NG2+ cell staining, R. Dutta (Cleveland Clinic Lerner Research Institute) for advice regarding protein extraction from human tissues and B. Popko (University of Chicago) for providing Plp1-creER mice. Human samples were provided by R. Bowser (Barrow Neurological Institute), K. Trevor (SACTL-VA Biorepository Trust), T. Hyde (Lieber Institute for Brain Development and the Johns Hopkins School of Medicine), J. Glass (Emory Alzheimer's Disease Research Center, 5P50AG025688-07), and the Johns Hopkins School of Medicine Department of Neuropathology. We thank E. Mosmiller for helping with patient demographic information. We also thank A. Agarwal and A. Langseth for critical discussions. This work was supported by grants from P2ALS (D.E.B. and J.D.R.), the US National Institutes of Health (NS27036 to D.W.C., NS33958 to J.D.R. and NS051509 to D.E.B.), the ALS Association (4ZMUDE to Y.L.), the Robert Packard Center for ALS Research at Johns Hopkins, and the Brain Science Institute.

Author information

Author notes

  1. Shin H Kang

    Present address: Present address: Shriners Hospital Pediatric Research Center, Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.,

  2. Shin H Kang and Ying Li: These authors contributed equally to this work.

Authors and Affiliations

  1. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Shin H Kang, Ileana Lorenzini, Jeffrey D Rothstein & Dwight E Bergles

  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Ying Li, Lyle W Ostrow & Jeffrey D Rothstein

  3. Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Japan

    Masahiro Fukaya

  4. Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Ileana Lorenzini, Lyle W Ostrow & Jeffrey D Rothstein

  5. Ludwig Institute, University of California, San Diego, California, USA

    Don W Cleveland

Authors
  1. Shin H Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masahiro Fukaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ileana Lorenzini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Don W Cleveland
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lyle W Ostrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeffrey D Rothstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dwight E Bergles
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.H.K., Y.L., J.D.R. and D.E.B. designed the experiments. S.H.K. carried out the experiments involving NG2+ cell proliferation, cell fate analysis of NG2+ cells and oligodendrocytes, and immunohistochemical analysis of oligodendrocyte structure (Figs. 1,2,3,4,5,6 and Supplementary Figs. 1–3 and 5). Y.L. performed western blot analysis from SOD1 (G93A) mice (Supplementary Fig. 7) and ALS patients (Supplementary Fig. 8), histological analysis of human tissue (Fig. 7), analysis of ricin-injected mice (Supplementary Fig. 4), and analysis of the SOD1 (G37R)–deleted mice (Fig. 8 and Supplementary Fig. 9). M.F. performed the electron microscopic and immunogold analysis (Fig. 6 and Supplementary Fig. 6). I.L. assisted with the ricin injections. D.W.C. provided the loxSOD1 (G37R) mice. L.W.O. provided assistance with analysis of the human ALS samples. S.H.K., Y.L., J.D.R. and D.E.B. wrote the manuscript.

Corresponding authors

Correspondence to Jeffrey D Rothstein or Dwight E Bergles.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Table 1 (PDF 3864 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kang, S., Li, Y., Fukaya, M. et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 16, 571–579 (2013). https://doi.org/10.1038/nn.3357

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3357

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing