Axonal pathology in demyelinating diseases

The eponym Charcot-Marie-Tooth disease (CMT) itself underscores that dominantly inherited neuropathies have been recognized for more than a century. CMT was separated into demyelinating (CMT1) and axonal (CMT2) types 80 years later by clinical, electrophysiological, and structural features. Several years ago, mutations in three genes, peripheral myelin protein 22 kd (PMP22), protein zero, and connexin32, were shown to cause CMT1A, CMT1B, and CMTX, respectively, and collectively account for most CMT1 patients. Because the proteins encoded by these genes are expressed by myelinating Schwann cells, the effects of mutant proteins are probably cell autonomous, initially affecting the myelinating Schwann cells themselves. Different mutant proteins have different effects, ranging from a loss of functional protein to toxic effects that transcend a simple loss of function and result in a more severe clinical phenotype. CMT1A is the most common form of CMT1 and is usually caused by inheritance of a 1.5-mB duplication within chromosome 17 that arose by unequal crossing over during meiosis. Inheritance of a chromosome 17 that lacks the same 1.5-mB region results in hereditary neuropathy with liability to pressure palsies (HNPP). This 1.5-mB region harbors the PMP22 gene, so that individuals with CMT1A have three copies of PMP22, and individuals with HNPP have one copy. HNPP is clinically distinct from CMT1A: affected individuals often develop acute focal neuropathies, typically at common sites of nerve entrapment, and have an underlying demyelinating neuropathy that is much milder than in CMT1A. How the duplication and deletion of PMP22 cause their respective clinical diseases, CMT1A and HNPP, is unresolved. The prevailing view is that even minor perturbations in the levels of PMP22 protein disturb the stability of compact myelin, which is envisioned to be a liquid crystal of highly ordered proteins and lipids, as PMP22 protein appears to be overexpressed in CMT1A and underexpressed in HNPP. Haneman and Muller have proposed an alternative view: both overexpression and underexpression of PMP22 result in demyelination because PMP22 acts like a growth arrest gene in Schwann cells. Demyelination alone, however, does not fully account for the pathogenesis of inherited demyelinating neuropathies. Slow nerve conduction velocities are not responsible for the main clinical manifestations, as children with CMT1 have slow conduction velocities before they are symptomatic, and velocities remain largely unchanged even as patients develop signs and symptoms of neuropathy. Rather, the number of motor axons innervating weak muscles is severely reduced, indicating that axonal loss is the cause of age-related weakness and atrophy. This inference is supported by anatomical evidence of progressive, length-dependent axonal loss in CMT1. Axonal loss is also a prominent feature of acquired demyelinating diseases, including Guillain-Barré syndrome, chronic inflammatory demyelinating neuropathy, and multiple sclerosis, so that axonal loss, and not demyelination or incomplete remyelination, may be the chief cause of chronic neurological dysfunction in affected individuals. How does demyelination cause axonal loss? There are no answers yet, but several clues have emerged from the careful examination of axon-glia interactions in animal models of inherited demyelinating diseases. Brady and colleagues have shown several alterations in the axonal cytoskeleton in Trembler (Tr) mice, which have a severe, dominantly inherited, demyelinating neuropathy caused by a missense mutation in Pmp22. Tr axons are thinly myelinated, and contain neurofilaments that are more closely packed and less phosphorylated than those in normal myelinated axons. In addition, the rate of axonal transport is altered in Tr nerves. Transplantation of Tr nerve grafts into normal mice demonstrates that the myelinating Tr Schwann cells, rather than the Tr axons themselves, initiate these axonal changes. The packing and phosphorylation of axonal neurofilaments also appear to be similarly altered in most, if not all, inherited demyelinating peripheral neuropathies, further supporting the idea that these alterations are linked to the cause of axonal loss. Pathological changes have also been found in central nervous system (CNS) axons of mice that have inherited abnormalities in the proteolipid protein gene, which encodes the major protein of CNS myelin. Highly packed, dephosphorylated neurofilaments are not strictly abnormal, however, as these are found in the stem process of large sensory neurons, which is an unmyelinated portion of an otherwise myelinated axon. It remains to be determined whether the altered axonal cytoskeleton of demyelinated axons is related to the axonal loss seen in demyelinating neuropathies. As reported in this issue, Sahenk and colleagues have made an important contribution to this problem, based on transplanting nerve grafts from CMT1A and HNPP patients as well as normal individuals. They grafted segments of sural nerves into nude mice, thereby avoiding immunological rejection of the xenografts, and examined the grafted segments 2 to 16