Schwann cells and the pathogenesis of inherited motor and sensory neuropathies (Charcot-Marie-Tooth disease)



Over the last 15 years, a number of mutations in a variety of genes have been identified that lead to inherited motor and sensory neuropathies (HMSN), also called Charcot-Marie-Tooth disease (CMT). In this review we will focus on the molecular and cellular mechanisms that cause the Schwann cell pathologies observed in dysmyelinating and demyelinating forms of CMT. In most instances, the underlying gene defects alter primarily myelinating Schwann cells followed by secondary axonal degeneration. The first set of proteins affected by disease-causing mutations includes the myelin components PMP22, P0/MPZ, Cx32/GJB1, and periaxin. A second group contains the regulators of myelin gene transcription EGR2/Krox20 and SOX10. A third group is composed of intracellular Schwann cells proteins that are likely to be involved in the synthesis, transport and degradation of myelin components. These include the myotubularin-related lipid phosphatase MTMR2 and its regulatory binding partner MTMR13/SBF2, SIMPLE, and potentially also dynamin 2. Mutations affecting the mitochondrial fission factor GDAP1 may indicate an important contribution of mitochondria in myelination or myelin maintenance, whereas the functions of other identified genes, including NDRG1, KIAA1985, and the tyrosyl-tRNA synthase YARS, are not yet clear. Mutations in GDAP1, YARS, and the pleckstrin homology domain of dynamin 2 lead to an intermediate form of CMT that is characterized by moderately reduced nerve conduction velocity consistent with minor myelin deficits. Whether these phenotypes originate in Schwann cells or in neurons, or whether both cell types are directly affected, remains a challenging question. However, based on the advances in systematic gene identification in CMT and the analyses of the function and dysfunction of the affected proteins, crucially interconnected pathways in Schwann cells in health and disease have started to emerge. These networks include the control of myelin formation and stability, membrane trafficking, intracellular protein sorting and quality control, and may extend to mitochondrial dynamics and basic protein biosynthesis. © 2006 Wiley-Liss, Inc.