Abstract
An insult to the mammalian spinal cord often results in persistent functional deficits. Proteins in CNS myelin are important determinants of this situation as they inhibit neurite growth. Among those proteins Nogo-A, oligodendrocyte myelin glycoprotein (OMgp), and myelin-associated glycoprotein (MAG) all bind to the neuronal Nogo-66 receptor (NgR1) and thereby block neuronal regeneration after injury. Neutralizing the interaction between the inhibitory ligands and NgR1 may alleviate the inhibition and therefore result in increased recovery after injury. Thus, antibodies neutralizing ligand/receptor interaction might have therapeutic value. From a set of 300 monoclonal anti-NgR1 antibodies one anti-NgR1 ligand blocking antibody (mAb50) was selected for in vivo studies. mAb50 binds with high affinity (below 100 pM) to human and rat NgR1, competes for binding of a ligand peptide (derived from Nogo-A: Nogo66) to the isolated NgR1 protein and cellular NgR1, and reduces the inhibitory effects of Nogo66 on neurite outgrowth in differentiated human NTera2 cells and rat dorsal root ganglion neurons. In a rat spinal cord hemisection model mAb50 enhanced functional locomotor recovery. These data suggest that neutralization of NgR1 activity with an antibody may be a valuable strategy to neutralize neurite outgrowth inhibition in the mammalian CNS. Thus anti-NgR1 antibodies are a potential approach for the treatment of spinal cord injury and even neurodegenerative diseases.
Highlights
In the adult mammalian central nervous system (CNS) the capability of repair after injury is limited
Proteins in CNS myelin are important determinants of this situation as they inhibit neurite growth. Among those proteins Nogo-A, oligodendrocyte myelin glycoprotein (OMgp), and myelin-associated glycoprotein (MAG) all bind to the neuronal Nogo-66 receptor (NgR1) and thereby block neuronal regeneration after injury
NgR1 interacts with the three myelin-associated inhibitors (MAIs) Nogo-A, MAG and OMgp [4,5,6,7,32,33]
Summary
In the adult mammalian central nervous system (CNS) the capability of repair after injury is limited. Intensive research efforts have sought to identify the cause of this lack of regenerative capabilities in adult CNS. It is accepted that injured nerve fibers in the CNS are intrinsically capable to regrow [2]. Inhibitory factors within the CNS actively prevent regrowth, and inhibit regeneration of the injured fiber tracts. CNS myelin is an important non-permissive factor causing growth cone collapse in vitro as well as in vivo, which results in the direct inhibition of axon outgrowth [3]. NgR1 is a GPI-anchored protein expressed in neurons of the adult CNS [9,10]. NgR1 and its analogue NgR3 are receptors for chondroitin sulfate proteogylcans (CSPGs)
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