Pharmacological induction of the heat shock response improves myelination in a n

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Neurobiol Dis. 2008 Jul 8.

Pharmacological induction of the heat shock response improves

myelination in a neuropathic model.

Rangaraju S, Madorsky I, Pileggi JG, Kamal A, Notterpek L.

Department of Neuroscience, College of Medicine, McKnight Brain

Institute, University of Florida, 100 Newell Drive, Box 100244,

Gainesville, FL 32610-0244, USA.

Misexpression and intracellular retention of peripheral myelin

protein 22 (PMP22) is associated with hereditary neuropathies in

humans, including Charcot-Marie-Tooth disease type 1A (CMT1A). Mice

expressing extra copies of the human PMP22, termed C22, display

morphologic and behavioral characteristics of CMT1A.

In neuropathic Schwann cells, the turnover of the newly-synthesized

PMP22 is decreased, leading to the formation of cytosolic protein

aggregates. To aid the processing of PMP22 and alleviate the

associated myelin defects, we pharmacologically stimulated the

expression of protein chaperones by synthetic small-molecule

inhibitors of heat shock protein 90 (HSP90).

The exposure of Schwann cells to these compounds enhanced the levels

of cytosolic chaperones in a time- and dose-dependent manner, with

minimal cytotoxicity. Treatment of dorsal root ganglion (DRG)

explants from neuropathic mice improved myelin formation and the

processing of PMP22. These results warrant further studies with HSP90

inhibitors as potential therapeutic candidates for hereditary

demyelinating neuropathies.