Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases

Abstract

For neurodegenerative diseases such as Huntington's disease, spinocerebellar muscular atrophy, amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease there is a lack of effective treatments that directly address the underlying biochemical aetiology of neuronal dysfunction and cell death. Protein misfolding, cellular stress and neuronal cell death are common features of neurodegenerative diseases. A diverse set of chaperone proteins act in concert to fold misfolded proteins, disaggregate damaged proteins and prevent programmed cell death. Heat shock transcription factor 1 (HSF1) coordinately activates the expression of chaperone protein gene expression. Genetic and pharmacological experiments in cell culture, fruitfly and mouse models of neurodegenerative disease suggest that enhancing the cellular protein folding and anti-apoptotic machinery by elevating levels of chaperone proteins could have potential therapeutic efficacy in neurodegenerative diseases. Current small-molecule HSF1 activators have undesirable properties — including direct proteotoxicity, inhibition of the central cellular chaperone heat shock protein 90 and other characteristics — that limit their development for clinical use. As the master activator of chaperone protein expression, HSF1 is an attractive pharmacological target for the development of optimized small-molecule activators for therapeutic intervention in neurodegenerative diseases.