title: Pharmacological induction of the heat shock response improves myelination in a neuropathic model.
abstract: 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.
authors.affiliation: Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610-0244, USA.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Rangaraju
authors.forename: Irina
authors.initials: I
authors.lastname: Madorsky
authors.forename: Jocelyn Go
authors.initials: JG
authors.lastname: Pileggi
authors.forename: Adeela
authors.initials: A
authors.lastname: Kamal
authors.forename: Lucia
authors.initials: L
authors.lastname: Notterpek
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002417:Cattle; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism* / Q000473:pathology; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D018869:Heat-Shock Response / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000502:physiology; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology*; D011247:Pregnancy; D051381:Rats
chemical_list: D018841:HSP90 Heat-Shock Proteins; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse