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

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. Access through your institution Buy or subscribe This is a preview

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GRP78/BIP/HSPA5 BINDS DIRECTLY TO TDP-43 AND MITIGATES TOXICITY ASSOCIATED WITH DISEASE PATHOLOGY Article Open access 17 May 2022 TARGETING CHAPERONE-MEDIATED AUTOPHAGY IN NEURODEGENERATIVE

DISEASES: MECHANISMS AND THERAPEUTIC POTENTIAL Article 15 November 2024 O-GLCNAC MODIFICATION OF SMALL HEAT SHOCK PROTEINS ENHANCES THEIR ANTI-AMYLOID CHAPERONE ACTIVITY Article 15 March

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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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 Authors * Daniel W. Neef View author publications

You can also search for this author inPubMed Google Scholar * Alex M. Jaeger View author publications You can also search for this author inPubMed Google Scholar * Dennis J. Thiele View

author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Dennis J. Thiele. ETHICS DECLARATIONS COMPETING INTERESTS 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. RELATED LINKS RELATED LINKS FURTHER INFORMATION Dennis J. Thiele's homepage ClinicalTrials.gov website 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE

THIS ARTICLE 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).

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