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Hsp70

Protein Inhibitor Helps Rid Brain Of Toxic Tau Protein
ScienceDaily (Sep. 30, 2009)
Inhibiting the protein Hsp70 rapidly reduces brain levels of tau, a protein associated with Alzheimer's disease when it builds up abnormally inside nerve cells affecting memory, neuroscientists at the University of South Florida found. The study is reported online September 29 in the Journal of Neuroscience...

One of the more effective Hsp70-inhibitor drugs the researchers discovered was a derivative of methylthioninium chloride, or Remberô, the first experimental medication reported to directly attack the tau tangles in patients with Alzheimer's disease. Remberô was heralded as a major development in the fight against Alzheimer's when results in early clinical trials were announced last year at the International Conference on Alzheimer's disease.

But Remberô and its derivatives do have some inherent problems; they're not very potent so effective therapy would require fairly high doses, Dickey said.

"The drug does help prevent the protein (tau) from clumping together, but that in itself doesn't mean it's actively getting rid of the toxic tau," he said. "Now that we know Hsp70 is a target of Remberô, we can develop similarly-acting drugs that will more specifically target this chaperone protein in affected areas of the brain, resulting in fewer side effects."...
http://www.sciencedaily.com/releases/2009/09/090929181808.htm

Protein inhibitor helps rid brain of toxic tau protein
University of South Florida Health [press release]

Inhibiting the protein Hsp70 rapidly reduces brain levels of tau, a protein associated with Alzheimer's disease when it accumulates as memory-choking tangles. One of the more effective Hsp70-inhibitor drugs was a derivative of methylthioninium chloride, or Rember, the laboratory study by neuroscientists at the University of South Florida found.

University of South Florida Health
http://www.eurekalert.org/pub_releases/2009-09/uosf-pih092809.php

Chemical Manipulation of Hsp70 ATPase Activity Regulates Tau Stability
The Journal of Neuroscience
September 30, 2009
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.
The Journal of Neuroscience, 29(39):12079-12088; doi:10.1523/JNEUROSCI.3345-09.2009
PubMed ID#: 19793966
http://www.jneurosci.org/cgi/content/abstract/29/39/12079



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