Nogo-66 receptor antagonist peptide promotes axonal regeneration.
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 oligodendrocytes and can inhibit axonal outgrowth through an axonal Nogo-66 receptor (NgR). The IN-1 monoclonal antibody recognizes Nogo-A and promotes corticospinal tract regeneration and locomotor recovery; 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.
GrandPré
Tadzia
T
Department of Neurology and Section of Neurobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Li
Shuxin
S
Strittmatter
Stephen M
SM
D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D001667:Binding, Competitive; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D058851:GPI-Linked Proteins; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects; D009185:Myelin Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D009186:Myelin Sheath / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D000070816:Nogo Receptor 1; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology
D017077:Culture Media, Conditioned; D058851:GPI-Linked Proteins; D009185:Myelin Proteins; C457761:NEPI-40 protein, rat; D000070816:Nogo Receptor 1; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C486581:Rtn4r protein, rat