Schwann cells and the pathogenesis of CMT

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Glia. 2006 Jul 19

Schwann cells and the pathogenesis of inherited motor and sensory

neuropathies (Charcot-Marie-Tooth disease).

Berger P, Niemann A, Suter U.

Institute of Cell Biology, Department of Biology, ETH Zurich, Zurich,

Switzerland.

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.