Targeting the Nogo Receptor Complex in Diseases of the Central Nervous System

C.      L. McDonald; C.      Bandtlow; M.      Reindl

Abstract

After injury to the central nervous system intrinsic factors such as myelin associated inhibitory factors inhibit cellular and axonal regeneration resulting in permanent disability. Three of these factors (Nogo-A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein) bind to a common receptor: the Nogo-66 receptor (NgR1). NgR1 is expressed mainly on neurons and is usually associated in a trimolecular complex. The second member of the complex, LINGO-1, is often connected to NgR1 function and is further found to function independently as a negative regulator of oligodendrocyte proliferation and differentiation. The third member of the NgR complex is either the p75 neurotrophin receptor, TROY, or an as yet unidentified co-receptor. Targeting of factors contained in this complex has been described to lead to the promotion of neurite outgrowth, oligodendrocyte proliferation and differentiation and inhibition of cell death. In the current review, we aim to describe the mechanisms of action of the chemical and biological compounds used in targeting NgR1 and LINGO-1. This will be achieved using three examples: blocking of ligand binding to NgR1 in treatment of spinal cord injury, antibody-mediated inhibition of LINGO-1 to promote oligodendrocyte differentiation in multiple sclerosis, and the use of soluble NgR1 to sequester Abeta peptide in the periphery in Alzheimers disease.

Keywords: Alzheimer's disease, LINGO-1, multiple sclerosis, myelin associated inhibitory factors, nogo receptor, spinal cord injury, central nervous system intrinsic, oligodendrocyte mye-lin glycoprotein, glycoprotein, oli-godendrocyte, sclerosis, chondroitin sulphate proteoglycans, glycosylphosphatidylinositol, hippocampal neurons, Purkinje cells, neurotrophin receptor, hybridization, immunohistochemis-try, oligodendrocyte precursor, myelination, alka-line phosphatase (AP), guanosine triphosphatase, blood-brain barrier, Schwann cell grafts, olfactory nervous system, erythropoietin, minocyclin, intravenous steroids, remyelination, corticospinal tract, thoracic spinal cord, serotonergic axon, amyloid peptide, mutagenesis, Multiple Sclerosi, Interferon-s, glatiramir acetate, glucocorticosteroids, proteolipid protein, Parkinson's disease, B lymphocyte stimulator