Axonal pathology in myelin disorders

Myelination provides extrinsic trophic signals that influence normal matura tion and long-term survival of axons. The extent of axonal involvement in d iseases affecting myelin or myelin forming cells has traditionally been und erestimated. There are, however, many examples of axon damage as a conseque nce of dysmyelinating or demyelinating disorders. More than a century ago, Charcot described the pathology of multiple sclerosis (MS) in terms of demy elination and relative sparing of axons. Recent reports demonstrate a stron g correlation between inflammatory demyelination in MS lesions and axonal t ransection, indicating axonal loss at disease onset. Disruption of axons is also observed in experimental allergic encephalomyelitis and in Theiler's murine encephalomyelitis virus disease, two animal models of inflammatory d emyelinating CNS disease. A number of dysmyelinating mouse mutants with axo nal pathology have provided insights regarding cellular and molecular mecha nisms of axon degeneration. For example, the myelin-associated glycoprotein and proteolipid protein have been shown to be essential for mediating myel in-derived trophic signals to axons. Patients with the inherited peripheral neuropathy Charcot-Marie Tooth disease type 1 develop symptomatic progress ive axonal loss due to abnormal Schwann cell expression of peripheral myeli n protein 22. The data summarized in this review indicate that axonal damag e is an integral part of myelin disease, and that loss of axons contributes to the irreversible functional impairment observed in affected individuals . Early neuroprotection should be considered as an additional therapeutic o ption for these patients.