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.

  • Article
  • Published:

LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis

Abstract

Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain–containing, Nogo receptor–interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.

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

Access options

Buy this article

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

Figure 1: Lower EAE clinical scores and increased remyelination in MOG-induced EAE Lingo1-knockout mice.
Figure 2: Treatment with an antibody antagonist to LINGO-1 function leads to functional recovery and increased integrity of axons in MOG-induced EAE rats.
Figure 3: Histochemical detection of remyelination after LINGO-1 antibody treatment.
Figure 4: Electron microscopic visualization of remyelination after anti-LINGO-1 treatment.

Similar content being viewed by others

References

  1. Trapp, B.D., Ransohoff, R.M., Fisher, E. & Rudick, R. Neurodegeneration in multiple sclerosis: relationship to neurological disability. Neuroscientist 5, 48–57 (1999).

    Article  Google Scholar 

  2. Noseworthy, J.H., Gold, R. & Hartung, H.P. Treatment of multiple sclerosis: recent trials and future perspectives. Curr. Opin. Neurol. 12, 279–293 (1999).

    Article  CAS  Google Scholar 

  3. Diem, R. et al. Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 128, 375–385 (2005).

    Article  Google Scholar 

  4. DuboisDalcq, M., ffrench-Constant, C. & Franklin, R.J.M. Enhancing central nervous system remyelination in multiple sclerosis. Neuron 48, 9–12 (2005).

    Article  CAS  Google Scholar 

  5. Mi, S. et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat. Neurosci. 7, 221–228 (2004).

    Article  CAS  Google Scholar 

  6. Mi, S. et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat. Neurosci. 8, 745–751 (2005).

    Article  CAS  Google Scholar 

  7. Lee, X. et al. NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation and myelination. J. Neurosci. 27, 220–225 (2007).

    Article  CAS  Google Scholar 

  8. Wekerle, H., Kojima, K., Lannes-Vieira, J., Lassmann, H. & Linington, C. Animal models. Ann. Neurol. 36 Suppl, S47–S53 (1994).

    Article  CAS  Google Scholar 

  9. Kerschensteiner, M. et al. Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis. J. Exp. Med. 200, 1027–1038 (2004).

    Article  CAS  Google Scholar 

  10. Reynolds, R. et al. The response of NG-2 expressing oligodendrocyte progenitors to demyelination in MOG-EAE and MS. J. Neurocytol. 31, 523–536 (2002).

    Article  Google Scholar 

  11. Ben-Hur, T. et al. Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia 41, 73–80 (2003).

    Article  Google Scholar 

  12. Lubetzki, C., Williams, A. & Stankoff, B. Promoting repair in multiple sclerosis: problems and prospects. Curr. Opin. Neurol. 18, 237–244 (2005).

    Article  CAS  Google Scholar 

  13. Ludwin, S.K. & Johnson, E. Evidence for a “dying-back” gliopathy in demyelinating disease. Ann. Neurol. 9, 301–305 (1981).

    Article  CAS  Google Scholar 

  14. Lassmann, H., Bartsch, U., Montag, D. & Schachner, M. Dying-back oligodendrogliopathy: a late sequel of myelin-associated glycoprotein deficiency. Glia 19, 104–110 (1997).

    Article  CAS  Google Scholar 

  15. Trapp, B.D. et al. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).

    Article  CAS  Google Scholar 

  16. Papadopoulos, D., Pham-Dinh, D. & Reynolds, R. Axon loss is responsible for chronic neurological deficit following inflammatory demyelination in the rat. Exp. Neurol. 197, 373–385 (2006).

    Article  CAS  Google Scholar 

  17. Kornek, B. et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol. 157, 267–276 (2000).

    Article  CAS  Google Scholar 

  18. Zhao, C., Fancy, S.P.J., Kotter, M.R., Li, W.W. & Franklin, R.J.M. Mechanisms of CNS remyelination—the key to therapeutic advances. J. Neurol. Sci. 233, 87–91 (2005).

    Article  CAS  Google Scholar 

  19. Eager, K.B. & Kennett, R.H. The use of conventional antisera in the production of specific monoclonal antibodies. J. Immunol. Methods 64, 157–164 (1983).

    Article  CAS  Google Scholar 

  20. Wu, W., Scott, D.E. & Reiter, R.J. Transplantation of mammalian pineal gland: studies of survival, revascularization, reinnervation, and recovery of function. Exp. Neurol. 122, 88–99 (1993).

    Article  CAS  Google Scholar 

  21. Li, L. et al. Rescue of adult mouse motoneurons from injury-induced cell death by a glial cell line-derived neurotrophic factor (GDNF). Proc. Natl. Acad. Sci. USA 92, 9771–9775 (1995).

    Article  CAS  Google Scholar 

  22. Hasan, K.M., Gupta, R.K., Santos, R.M., Wolinsky, J.S. & Narayana, P.A. Comparison of gradient encoding schemes for diffusion-tensor MRI. J. Magn. Reson. Imaging 13, 769–780 (2001).

    Article  CAS  Google Scholar 

  23. Basser, P.J. & Pierpaoli, C. Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J. Magn. Reson. B. 111, 209–219 (1996).

    Article  CAS  Google Scholar 

  24. Kim, J.H. et al. Detecting axon damage in spinal cord from a mouse model of multiple sclerosis. Neurobiol. Dis. 21, 626–632 (2006).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Sha Mi or Wutian Wu.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–5, Supplementary Methods (PDF 221 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mi, S., Hu, B., Hahm, K. et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med 13, 1228–1233 (2007). https://doi.org/10.1038/nm1664

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1664

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