Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.
Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.
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DOI：
10.1371/journal.pbio.1000291
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发表时间：
2010-01-19
期刊：
影响因子：
9.8
通讯作者：
Thiele DJ
中科院分区：
文献类型：
--
作者：
Neef DW;Turski ML;Thiele DJ
A yeast-based small molecule screen identifies a novel activator of human HSF1 and protein chaperone expression and which appears to alleviate the toxicity of protein misfolding diseases. Neurodegenerative diseases such as Huntington disease are devastating disorders with no therapeutic approaches to ameliorate the underlying protein misfolding defect inherent to poly-glutamine (polyQ) proteins. Given the mounting evidence that elevated levels of protein chaperones suppress polyQ protein misfolding, the master regulator of protein chaperone gene transcription, HSF1, is an attractive target for small molecule intervention. We describe a humanized yeast-based high-throughput screen to identify small molecule activators of human HSF1. This screen is insensitive to previously characterized activators of the heat shock response that have undesirable proteotoxic activity or that inhibit Hsp90, the central chaperone for cellular signaling and proliferation. A molecule identified in this screen, HSF1A, is structurally distinct from other characterized small molecule human HSF1 activators, activates HSF1 in mammalian and fly cells, elevates protein chaperone expression, ameliorates protein misfolding and cell death in polyQ-expressing neuronal precursor cells and protects against cytotoxicity in a fly model of polyQ-mediated neurodegeneration. In addition, we show that HSF1A interacts with components of the TRiC/CCT complex, suggesting a potentially novel regulatory role for this complex in modulating HSF1 activity. These studies describe a novel approach for the identification of new classes of pharmacological interventions for protein misfolding that underlies devastating neurodegenerative disease. The misfolding of proteins into a toxic state contributes to a variety of neurodegenerative diseases such as Huntington, Alzheimer, and Parkinson disease. Although no known cure exists for these afflictions, many studies have shown that increasing the levels of protein chaperones, proteins that assist in the correct folding of other proteins, can suppress the neurotoxicity of the misfolded proteins. As such, increasing the cellular concentration of protein chaperones might serve as a powerful therapeutic approach in treating protein misfolding diseases. Because the levels of protein chaperones in the cell are primarily controlled by the heat shock transcription factor 1 [HSF1], we have designed and implemented a pharmacological screen to identify small molecules that can promote human HSF1 activation and increase the expression of protein chaperones. Through these studies, we have identified HSF1A, a molecule capable of activating human HSF1, increasing the levels of protein chaperones and alleviating the toxicity of misfolded proteins in both cell culture as well as fruit fly models of neurodegenerative disease.
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影响因子：
64.5
作者：
Dai, Chengkai;Whitesell, Luke;Lindquist, Susan
通讯作者：
Lindquist, Susan
影响因子：
4.8
作者：
Auluck, PK;Meulener, MC;Bonini, NM
通讯作者：
Bonini, NM
影响因子：
3.5
作者：
Emter, R;Heese-Peck, A;Kralli, A
通讯作者：
Kralli, A
DOI：
10.1196/annals.1391.005
发表时间：
2007-01-01
期刊：
STRESS RESPONSES IN BIOLOGY AND MEDICINE
影响因子：
--
作者：
Akerfelt, Malin;Trouillet, Diane;Sistonen, Lea
通讯作者：
Sistonen, Lea
影响因子：
2.5
作者：
HIRATA, D;YANO, K;MIYAKAWA, T
通讯作者：
MIYAKAWA, T