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

Nature Reviews Drug Discovery volume 10, pages 930–944 (2011)Cite this article

Subjects

Key Points

  • 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.

Abstract

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion-based neurodegeneration are associated with the accumulation of misfolded proteins, resulting in neuronal dysfunction and cell death. However, current treatments for these diseases predominantly address disease symptoms, rather than the underlying protein misfolding and cell death, and are not able to halt or reverse the degenerative process. Studies in cell culture, fruitfly, worm and mouse models of protein misfolding-based neurodegenerative diseases indicate that enhancing the protein-folding capacity of cells, via elevated expression of chaperone proteins, has therapeutic potential. Here, we review advances in strategies to harness the power of the natural cellular protein-folding machinery through pharmacological activation of heat shock transcription factor 1 — the master activator of chaperone protein gene expression — to treat neurodegenerative diseases.

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Figure 1: Chaperone proteins and maintenance of protein homeostasis.
Figure 2: HSF1 activation and attenuation cycle.
Figure 3: HSF1 regulation by post-translational modifications.
Figure 4: Proposed mechanisms to promote the direct activation of HSF1.
Figure 5: Importance of early intervention in neurodegenerative diseases.

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Acknowledgements

We thank T. Nevitt for her critical comments on the manuscript. This work was supported in part by the US National Institutes of Health (NIH) National Research Service Award Postdoctoral Fellowship GM076954 (to D.W.N.) and the NIH grant R01-GM059911 (to D.J.T.). A.M.J. is a trainee of the Duke University Pharmacological Sciences Training Program.

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  1. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, 27710, North Carolina, USA

    Daniel W. Neef, Alex M. Jaeger & Dennis J. Thiele

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Dennis J. Thiele and Daniel W. Neef are inventors on patent applications describing small-molecule activators of human heat shock transcription factor 1. Dennis J. Thiele is a co-founder and a shareholder of Chaperone Therapeutic, Inc.

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Glossary

Dyskinesia

A condition in which voluntary movement is lost and an increase in chorea-like involuntary movement is observed.

Leucine zipper

A structural motif that stabilizes inter- or intramolecular protein–protein interactions via hydrophobic and charged interactions across coiled-coils and is commonly found in oligomerization domains.

Sumoylation

A post-translational modification that is indicated by the addition of a small ubiquitin-like modifier (SUMO) moiety that can affect protein stability, localization and activity.

Residence time

The duration of time that heat shock transcription factor 1 is bound to heat shock elements in the promoter region of target genes such as those encoding chaperone proteins.

Chaperone-mediated autophagy

A process by which cytosolic proteins are selectively degraded through interaction with heat shock cognate protein 70, which facilitates direct translocation into lysosomes for proteolysis.

Unfolded protein response

A conserved physiological response involving endoplasmic reticulum (ER)-initiated signal-transduction events, induced by accumulation of unfolded proteins in the lumen of the ER.

SOD1G93A mice

Transgenic mice expressing the G93A mutant form of human superoxide dismutase 1 (SOD1) that causes familial amyotrophic lateral sclerosis (ALS), which are commonly used as a model for ALS.

RNA aptamer

A specifically designed oligonucleotide with a secondary structure that elicits high affinity for a desired target.

p53R172H mouse model

A mouse model expressing a mutated form of the tumour suppressor protein p53, R172H, which results in increased oncogenesis.

R6/2 mouse model

A widely used transgenic mouse model — expressing exon 1 of the human huntingtin gene containing 150 CAG repeats — that rapidly develops Huntington's disease-like symptoms.

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Neef, D., Jaeger, A. & Thiele, D. Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat Rev Drug Discov 10, 930–944 (2011). https://doi.org/10.1038/nrd3453

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