Pharmacological induction of the heat shock response improves myelination in a neuropathic model

NEUROBIOLOGY OF DISEASE

卷:32

Article

Rangaraju, Sunitha¹  Madorsky, Irina¹  Pileggi, Jocelyn Go¹  Kamal, Adeela²  Notterpek, Lucia¹ 

[1] Univ Florida, McKnight Brain Inst, Coll Med, Dept Neurosci, Gainesville, FL 32610 USA

[2] Biogen Idec, San Diego, CA 92122 USA

关键词: CMT1A neuropathy;    demyelination;    Schwann cells;    protein misfolding;    heat shock response;    heat shock proteins;    HSP90 inhibitors;    myelination;    myelin, peripheral myelin protein 22;   

DOI  :  10.1016/j.nbd.2008.06.015

来源: Elsevier

【 摘 要 】

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. (C) 2008 Elsevier Inc. All rights reserved.

【 授权许可】

Free