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Featured ArticleArticles, Neurobiology of Disease

Chemical Manipulation of Hsp70 ATPase Activity Regulates Tau Stability

Umesh K. Jinwal, Yoshinari Miyata, John Koren III, Jeffrey R. Jones, Justin H. Trotter, Lyra Chang, John O'Leary, David Morgan, Daniel C. Lee, Cody L. Shults, Aikaterini Rousaki, Edwin J. Weeber, Erik R. P. Zuiderweg, Jason E. Gestwicki and Chad A. Dickey
Journal of Neuroscience 30 September 2009, 29 (39) 12079-12088; DOI: https://doi.org/10.1523/JNEUROSCI.3345-09.2009
Umesh K. Jinwal
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Yoshinari Miyata
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John Koren III
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Jeffrey R. Jones
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Justin H. Trotter
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Lyra Chang
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John O'Leary
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David Morgan
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Daniel C. Lee
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Cody L. Shults
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Aikaterini Rousaki
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Edwin J. Weeber
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Erik R. P. Zuiderweg
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Jason E. Gestwicki
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Chad A. Dickey
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Abstract

Alzheimer's disease and other tauopathies have recently been clustered with a group of nervous system disorders termed protein misfolding diseases. The common element established between these disorders is their requirement for processing by the chaperone complex. It is now clear that the individual components of the chaperone system, such as Hsp70 and Hsp90, exist in an intricate signaling network that exerts pleiotropic effects on a host of substrates. Therefore, we have endeavored to identify new compounds that can specifically regulate individual components of the chaperone family. Here, we hypothesized that chemical manipulation of Hsp70 ATPase activity, a target that has not previously been pursued, could illuminate a new pathway toward chaperone-based therapies. Using a newly developed high-throughput screening system, we identified inhibitors and activators of Hsp70 enzymatic activity. Inhibitors led to rapid proteasome-dependent tau degradation in a cell-based model. Conversely, Hsp70 activators preserved tau levels in the same system. Hsp70 inhibition did not result in general protein degradation, nor did it induce a heat shock response. We also found that inhibiting Hsp70 ATPase activity after increasing its expression levels facilitated tau degradation at lower doses, suggesting that we can combine genetic and pharmacologic manipulation of Hsp70 to control the fate of bound substrates. Disease relevance of this strategy was further established when tau levels were rapidly and substantially reduced in brain tissue from tau transgenic mice. These findings reveal an entirely novel path toward therapeutic intervention of tauopathies by inhibition of the previously untargeted ATPase activity of Hsp70.

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The Journal of Neuroscience: 29 (39)
Journal of Neuroscience
Vol. 29, Issue 39
30 Sep 2009
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Chemical Manipulation of Hsp70 ATPase Activity Regulates Tau Stability
Umesh K. Jinwal, Yoshinari Miyata, John Koren III, Jeffrey R. Jones, Justin H. Trotter, Lyra Chang, John O'Leary, David Morgan, Daniel C. Lee, Cody L. Shults, Aikaterini Rousaki, Edwin J. Weeber, Erik R. P. Zuiderweg, Jason E. Gestwicki, Chad A. Dickey
Journal of Neuroscience 30 September 2009, 29 (39) 12079-12088; DOI: 10.1523/JNEUROSCI.3345-09.2009

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Chemical Manipulation of Hsp70 ATPase Activity Regulates Tau Stability
Umesh K. Jinwal, Yoshinari Miyata, John Koren III, Jeffrey R. Jones, Justin H. Trotter, Lyra Chang, John O'Leary, David Morgan, Daniel C. Lee, Cody L. Shults, Aikaterini Rousaki, Edwin J. Weeber, Erik R. P. Zuiderweg, Jason E. Gestwicki, Chad A. Dickey
Journal of Neuroscience 30 September 2009, 29 (39) 12079-12088; DOI: 10.1523/JNEUROSCI.3345-09.2009
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