Protection of oligodendrocyte precursor cells by low doses of HSP90 inhibitors in cell culture.
Oligodendrocyte precursor cells (OPCs) become myelin-forming after their differentiation into post-mitotic oligodendrocytes. OPCs are extremely efficient at myelin repair and contribute to remyelination. However, remyelination fails in multiple sclerosis (MS), which suggest that the OPCs are ineffective in this disorder. We have studied previously the expression of heat shock protein 90 (HSP90) in OPCs and have reported autoantibodies against HSP90 in MS patients, which recognize the antigen on the OPC surface. The present study investigated a protective effect of HSP90 inhibitors observed in cultured OPCs. Radicicol and 17-allylamino-17-demethoxygeldanamycin (17-AAG) at non-cytotoxic doses targeted cell-surface HSP90 in OPCs. Thus, 0.01 nM 17-AAG or 10 nM radicicol competed with the anti-HSP90 antibodies for binding to cell-surface HSP90. These low doses of HSP90 inhibitors prevented HSP90-antibody-induced OPC death and protected the oligodendrocyte population against antibody attack. Adult oligodendrocytes were protected by these low doses of HSP90 inhibitors in a similar fashion to perinatal cells. The present results show that, despite OPCs being very sensitive to HSP90 inhibitors, low and non-cytotoxic doses of 17-AAG and radicicol protect oligodendrocytes from anti-HSP90 antibody attack. They may have therapeutic potential for MS patients that have anti-HSP90 autoantibodies and provide a novel strategy for therapeutic intervention with HSP90 inhibitors.
Cid
Cristina
C
Center for Astrobiology, CSIC-INTA, Torrejon de Ardoz, Spain.
Alcazar
Alberto
A
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use; D018942:Macrolides / Q000494:pharmacology / Q000627:therapeutic use; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects* / Q000276:immunology; D009836:Oligodendroglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; C112765:tanespimycin; C035359:monorden