Myelin associated inhibitors; molecular mechanisms and therapeutic potential

Abstract

Whereas the peripheral nervous system can readily regenerate after injury, regeneration is very limited in the central nervous system of adult vertebrates. Over the past three decades, it has become clear that this lack of regeneration has a molecular basis. The myelin that provides electrical insulation of neuronal fibers has a different composition in the central nervous system, as compared to peripheral nervous system myelin. Several proteins expressed on myelin have been found to have inhibitory effects for neuronal regeneration and were dubbed myelin-associated inhibitors. The three classical myelin-associated inhibitors (Nogo, MAG and OMgp) were found to signal all three through two distinct receptor complexes, providing a puzzling redundancy for these interactions. This signaling is speculated to be important for stabilizing neuronal circuitry in healthy adult organisms. Other proteins known to be involved in axonal guidance, such as semaphorins, ephrins, netrins and Wnts, as well as extracellular matrix components such as the chondroitin sulfate proteoglycans, have also been shown to have regeneration inhibitory effects. Downstream signaling by neuronal effector proteins culminates in modulation of the cytoskeleton and transcription, explaining the morphological changes of the neurons that are observed upon signaling. The fact that the lack of regeneration has a molecular basis provides prospects for therapeutic intervention to stimulate regeneration for injuries of the central nervous system, like spinal cord injury or stroke. Indeed, a substantial body of different proteins, peptides and small molecules that intervene with the different steps involved in the inhibition of regeneration shows promising effects, both in vitro and in vivo.

This review will discuss the advances made on understanding the lack of regeneration in the central nervous system. After an introduction on the nervous system, injury and regeneration, the molecular mechanisms of inhibition will be discussed. A special focus will be on the three classical myelin associated inhibitors and their receptor complexes, but other molecules that are inhibitory for regeneration will be discussed as well. The current understanding of the downstream signaling cascades of the myelin associated inhibitors will be reviewed and finally, different strategies that demonstrate the therapeutic potential of interfering with these mechanisms will be discussed.