Nogo limits neural plasticity and recovery from injury

Abstract

The expression of Nogo-A and the receptor NgR1 limits the recovery of adult mammals from central nervous system injury. Multiple studies have demonstrated efficacy from targeting this pathway for functional recovery and neural repair after spinal cord trauma, ischemic stroke, optic nerve injury and models of multiple sclerosis. Recent molecular studies have added S1PR2 as a receptor for the amino terminal domain of Nogo-A, and have demonstrated shared components for Nogo-A and CSPG signaling as well as novel Nogo antagonists. It has been recognized that neural repair involves plasticity, sprouting and regeneration. A physiologic role for Nogo-A and NgR1 has been documented in the restriction of experience-dependent plasticity with maturity, and the stability of synaptic, dendritic and axonal anatomy.

Figure 1. Molecular Mechanisms Related to Nogo-A Signaling

The schematic illustrates the two growth inhibiting domains of Nogo-A, the Δ20 region and the Nogo-66 region. The two hydrophobic (HP1, HP2) segments are highlighted, as well as two adjacent regions (light green) that cooperate with Nogo-66 activity. The Δ20 region interacts with S1PR2, and the Nogo-66 region interacts with NgR1, and both can couple to RhoA and Rho-Associated Kinase (ROCK) signaling. Additional recent findings demonstrate that chondroitin sulfate proteoglycans (CSPGs) can inhibit growth via both NgR1 and NgR3, and that the LOTUS protein antagonizes Nogo-66 signaling. Further discussion and references are provided in the text.

Figure 2. Cellular Mechanisms of Neural Repair Limited by Nogo-A and NgR1

Injuries to the central nervous system of traumatic, ischemic or other etiology typically damage certain axonal pathways but spare parallel pathways. Recovery and repair can be supported by a range of cellular events, here grouped into three main mechanisms. The cut axon can grow back over long distances by regeneration, or uninjured and injured fibers that are rostral and caudal to the injury can sprout to form new connections, or plastic changes of presynaptic and postsynaptic connections throughout the nervous system. Data show that Nogo-A and NgR1 limit all three of these mechanisms, and blockade of their action supports repair and recovery. Further discussion and references are provided in the text.