Phosphoinositides and Charcot-Marie-tooth disease: new keys to old questions

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Cell Mol Life Sci. 2007 Dec;64(24):3261-5.

Phosphoinositides and Charcot-Marie-tooth disease: new keys to old

questions.

Suter U.

Institute of Cell Biology, Department of Biology, ETH Zürich, ETH-

Hönggerberg, 8093, Zürich, Switzerland.

Recent research into the genetic basis and the molecular disease

mechanisms of Charcot-Marie-Tooth disease (CMT), also called

hereditary motor and sensory neuropathies, has highlighted

phosphoinositides, membrane-tethered phosphorylated metabolites of

phosphatidylinositol, as key regulatory molecules in peripheral

nerves in health and disease. Enzymes that dephosphorylate the

endosomal phosphoinositides phosphatidylinositol-3-phosphate and/or

phosphatidylinositol-3,5-biphosphate, and proteins with binding

domains for these phosphoinositides, are mutated in subtypes of CMT.

A hypothetical picture emerges suggesting that the precise regulation

of phosphoinositide levels within neural cells, a process in turn

critical for the correct dynamics of proteins binding to

phosphoinositides, is a crucial bottleneck for the accurate function

of myelinated peripheral nerves in both neurons and Schwann cells.

The underlying molecular and cellular mechanisms are largely unknown.

Some hypotheses are discussed in this essay.