Dominantly inherited demyelinating neuropathies, known as Charcot-Marie-Tooth disease type 1 (CMTI), are among the most common inherited neurological diseases. CMTI is caused by mutations in one of several genes that are expressed by myelinating Schwann cells, including PMP22, MPZ, and GJBJ. Although demyelination is the first pathological consequence, axonal loss rather than demyelination per se, is the main cause of neurologic disability. In this grant, we will evaluate the consequences of disrupted axon-Schwann cell interactions in demyelinating neuropathies, by determining whether demyelination and remyelination reorganize the axonal membrane in (i) several animal models of inherited demyelinating neuropathy, and in (ii) an animal model of acute demyelination (after lysolecithin injection into the sciatic nerve). In this way, we will determine whether different genetic causes of demyelination have similar effects on the molecular organization of axonal membranes, and the temporal order in which the molecular components of nodes, paranodes, and juxtaparanodes are disassembled by demyelination and reassembled during remyelination. We will also determine whether axonal loss in demyelinating neuropathies can be ameliorated in two ways-by breeding Mpz/Po-null and Pmp22-null mice with either Wids or transgenic mice in which glial-derived neurotrophic factor (GDNF) is overexpressed in muscle. If expressing the Wlds gene or the GDNF-transgene preserves axons Mpz/Po-null and Pmp22-null mice, this will provide proof of the concept that therapies directed at neurons rather than myelinating Schwann cells can be effective treatments for inherited demyelinating neuropathies.
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