Control of de-myelination by the c-Jun pathway: implications for peripheral neuropathies.

Malfunction of peripheral nerves (neuropathy) due to faulty genes (inherited neuropathies) or to inflammation caused by bacteria or viruses (acquired neuropathies) is relatively common, and results in serious muscle weakness and/or paralysis and loss of sensation. This is due to the loss of an insulating cover, the myelin sheath, from the nerve fibres and from damage to the fibres themselves. As a result, nerves are unable to communicate messages from the brain to muscles and from the skin and muscles back to the brain. The myelin sheath, which is made by Schwann cells, surrounds axons in the peripheral nervous system. It protects the nerve fibres and speeds up the rate at which messages are transmitted along them. Loss of the myelin sheaths, de-myelination, leads to a failure to transmit signals correctly and ultimately to the death of axons. We have recently identified a signalling pathway within the Schwann cells that has a central function in de-myelination caused by direct nerve injury. We wish to determine whether this novel negative regulator of myelination is also likely to be central to the de-myelination that is characteristic of hereditary and acquired neuropathies in humans. For this purpose, we will use well-characterized mouse models of these human conditions together with strategies that inhibit the signalling pathway to determine whether we can prevent de-myelination and improve nerve function. Positive findings would provide new strategies for treatment of human neuropathies for which, at present, there are no cures.

Myelinating Schwann cells, even in mature nerves, have the unusual property of being able to abandon their normal myelinated state and adopt instead an immature phenotype in a process that involves re-entry to the cell cycle and myelin breakdown. This de-differentiation and de-myelination is seen acutely in injured nerves but it is also the hallmark of two major classes of peripheral neuropathies, Charcot-Marie-Tooth type 1 (CMT1) and Guillain-Barre Syndrome, which can lead to severe weakness/paralysis. Currently, there is no cure for these diseases.
Although different adverse stimuli are at work in these three situations, it is likely that they ultimately impinge on a common intracellular mechanisms to trigger de-myelination and re-entry to the cell cycle. Recently, we and others have described intracellular signalling pathways that act as negative regulators of myelination. We have now found that blocking one of these pathways, the Jun-NH2-terminal kinase/c-Jun (JNK/c-Jun) pathway (by genetic ablation of c-Jun in vivo), strikingly arrests the classical Schwann cell de-myelination response (Wallerian degeneration) to nerve injury. We have also shown that this pathway is rapidly activated in injured nerves and that is required for Schwann cell proliferation. The main purpose of the present proposal is to determine whether this novel regulator of Schwann cell de-differentiation in injured nerves is likely also to be central to the de-myelination seen in CMT1 and Guillain-Barre Syndrome, a finding that would open new avenues for therapeutic intervention. To do this we will examine JNK/c-Jun activity in the major animal models of CMT1A, the most common type of CMT1, and Guillain-Barre Syndrome and determine whether inhibition of JNK/c-Jun ameliorates the de-myelination/dismyelination characteristic of these models. Positive results from these experiments would have significant clinical implications.