Induction of multiple heat shock proteins and neuroprotection in a primary culture model of familial amyotrophic lateral sclerosis.
High threshold for stress-induced activation of the heat shock transcription factor, Hsf1, may contribute to vulnerability of motor neurons to disease and limit efficacy of agents promoting expression of neuroprotective heat shock proteins (Hsps) through this transcription factor. Plasmid encoding a constitutively active form of Hsf1, Hsf1act, and chemicals shown to activate Hsf1 in other cells were investigated in a primary culture model of familial amyotrophic lateral sclerosis. Hsf1act and the Hsp90 inhibitor, geldanamycin, induced high expression of multiple Hsps in cultured motor neurons and conferred dramatic neuroprotection against SOD1G93A in comparison to Hsp70 or Hsp25 alone. Two other Hsp90 inhibitors, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and radicicol, and pyrrolidine dithiocarbamate induced robust expression of Hsp70 and Hsp40 in motor neurons, but at cytotoxic concentrations. 17-AAG, which penetrates the blood-brain barrier, has exhibited a higher therapeutic index than geldanamycin, but this may not be the case when activation of Hsf1 in neurons is targeted.
Batulan
Zarah
Z
Montreal Neurological Institute, McGill University, 3801 University St., Montreal, Quebec, Canada H3A 2B4.
Taylor
David M
DM
Aarons
Rebecca J
RJ
Minotti
Sandra
S
Doroudchi
Mohammad M
MM
Nalbantoglu
Josephine
J
Durham
Heather D
HD
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors; D050956:HSP40 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000633:toxicity; D013859:Thiocarbamates / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C000619706:HSF1 protein, human; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D018696:Neuroprotective Agents; D011759:Pyrrolidines; D013859:Thiocarbamates; D014157:Transcription Factors; C020972:pyrrolidine dithiocarbamic acid; C112765:tanespimycin; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C035359:monorden; C001277:geldanamycin