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Nogo-66 receptor antagonist peptide promotes axonal regeneration

Nature volume 417, pages 547–551 (2002)Cite this article

Abstract

Myelin-derived axon outgrowth inhibitors, such as Nogo, may account for the lack of axonal regeneration in the central nervous system (CNS) after trauma in adult mammals. A 66-residue domain of Nogo (Nogo-66) is expressed on the surface of oligodendrocytes1 and can inhibit axonal outgrowth through an axonal Nogo-66 receptor (NgR)2. The IN-1 monoclonal antibody recognizes Nogo-A and promotes corticospinal tract regeneration and locomotor recovery3,4,5; however, the undefined nature of the IN-1 epitope in Nogo, the limited specificity of IN-1 for Nogo, and nonspecific anti-myelin effects have prevented a firm conclusion about the role of Nogo-66 or NgR. Here, we identify competitive antagonists of NgR derived from amino-terminal peptide fragments of Nogo-66. The Nogo-66(1–40) antagonist peptide (NEP1–40) blocks Nogo-66 or CNS myelin inhibition of axonal outgrowth in vitro, demonstrating that NgR mediates a significant portion of axonal outgrowth inhibition by myelin. Intrathecal administration of NEP1–40 to rats with mid-thoracic spinal cord hemisection results in significant axon growth of the corticospinal tract, and improves functional recovery. Thus, Nogo-66 and NgR have central roles in limiting axonal regeneration after CNS injury, and NEP1-40 provides a potential therapeutic agent.

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Figure 1: NEP1–40 is a competitive antagonist of Nogo-66.
Figure 2: NEP1–40 partially blocks inhibitory activity of CNS myelin.
Figure 3: NEP1–40 promotes dorsal CST sprouting rostral to mid-thoracic dorsal hemisection.
Figure 4: Numerous regenerating CST fibres caudal to a mid-thoracic dorsal hemisection.
Figure 5: NEP1–40 promotes locomotor recovery after spinal cord injury.

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Acknowledgements

We thank Y. Fu for technical assistance. This work was supported by grants to S.M.S. from the NIH, the McKnight Foundation for Neuroscience, and Biogen Inc. T.G. is a Bayer Predoctoral Scholar and S.M.S. is an Investigator of the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

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Author notes

  1. Tadzia GrandPré and Shuxin Li: These authors contributed equally to this work

  2. Correspondence and requests for materials should be addressed to S.M.S. .

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  1. Tadzia GrandPré
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  2. Shuxin Li
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  3. Stephen M. Strittmatter
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Competing interests

Biogen Inc. supports this research in part and holds an option to license NgR technology from Yale University.

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Department of Neurology and Section of Neurobiology, Yale University School of Medicine, P.O. Box 208018, New Haven, Connecticut 06520, USA

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GrandPré, T., Li, S. & Strittmatter, S. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417, 547–551 (2002). https://doi.org/10.1038/417547a

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