K252a enhancement of myelin in CMT 1A and DSS

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Abstract from J Neurosci Res. 2004 Dec 16

Enhancement of Schwann cell myelin formation by K252a in the Trembler-J mouse

dorsal root ganglion explant culture.

Liu N, Varma S, Shooter EM, Tolwani RJ.

Department of Neurobiology, Stanford University School of Medicine, Stanford,

California.

The Trembler-J (TrJ) mouse, containing a point mutation in the peripheral myelin

protein 22 gene, is characterized by severe hypomyelination and is a

representative model of Charcot-Marie-Tooth 1A disease/Dejerine-Sottas Syndrome.

Previous studies have shown that protein kinase inhibitor K252a enhances

wild-type Schwann cell myelination in culture. We used a dorsal root ganglion

(DRG) explant culture system from the heterozygous TrJ/+ mouse to investigate if

myelination could be enhanced by K252a. The TrJ/+ DRG explant cultures

replicated some important features of the TrJ/+ mouse, showing reduced myelin

protein accumulation, thinner myelin sheaths, and shortened myelin internodes.

K252a increased myelin protein accumulation and myelin sheath thickness but did

not substantially increase myelin internode length. Furthermore, the TrJ/+ DRG

explant culture and sciatic nerves continued to respond to K252a during the

stage when myelination is complete in the wild type. A general tyrosine kinase

inhibitor, genistein, but not inhibitors of serine/threonine protein kinase

inhibitors, had a similar effect to K252a. K252a is therefore able to partially

overcome hypomyelination by enhancing mutant Schwann cell myelin formation in

the TrJ/+ mouse.