Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / metabolism*
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Amyotrophic Lateral Sclerosis / physiopathology
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Animals
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Benzoquinones / pharmacology
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Cells, Cultured
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Cytoprotection / drug effects
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Cytoprotection / genetics*
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DNA-Binding Proteins / genetics*
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics
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Genetic Vectors
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HSP40 Heat-Shock Proteins / antagonists & inhibitors
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HSP40 Heat-Shock Proteins / metabolism
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HSP70 Heat-Shock Proteins / antagonists & inhibitors
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HSP70 Heat-Shock Proteins / metabolism
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / metabolism
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Heat Shock Transcription Factors
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Heat-Shock Proteins / antagonists & inhibitors
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Humans
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Lactams, Macrocyclic / pharmacology
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Macrolides / pharmacology
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Mice
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Motor Neurons / drug effects
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Motor Neurons / metabolism*
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Motor Neurons / pathology
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Pyrrolidines / pharmacology
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Superoxide Dismutase / antagonists & inhibitors
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Superoxide Dismutase / toxicity
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Thiocarbamates / pharmacology
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Transcription Factors / genetics*
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Transfection
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Up-Regulation / drug effects
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Up-Regulation / genetics
Substances
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Benzoquinones
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DNA-Binding Proteins
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Enzyme Inhibitors
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HSF1 protein, human
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HSP40 Heat-Shock Proteins
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HSP70 Heat-Shock Proteins
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HSP90 Heat-Shock Proteins
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Heat Shock Transcription Factors
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Heat-Shock Proteins
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Lactams, Macrocyclic
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Macrolides
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Neuroprotective Agents
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Pyrrolidines
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Thiocarbamates
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Transcription Factors
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pyrrolidine dithiocarbamic acid
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tanespimycin
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SOD1 G93A protein
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Superoxide Dismutase
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monorden
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geldanamycin