A primary pathological component of Alzheimer's disease (AD) is the formation of neurofibrillary tangles (NFT) composed of hyper-phosphorylated tau (p-tau), a process closely linked to neurodegeneration. Expediting the removal of these p-tau species may be a highly relevant therapeutic stratagem. We have shown that inhibition of the ATPase activity of Hsp90 degrades p-tau independent of de novo chaperone transcription by heat shock factor-1;however multiple degradation pathways have been described for the tau protein, and these may hold equal importance with regard to the mechanisms underlying tau accumulation. Therefore we have begun investigating the mechanisms used by both the constitutive chaperone complex and novel independent pathways of degradation to facilitate the removal of abnormal p-tau. The Hsp90 complex typically works in concert with various interchangeable components (i.e. E3 ubiquitin ligases, prolyl isomerases, etc) culminating in either complete or partial re-folding of the substrate, or its degradation. While several components specifically involved in p-tau degradation have been identified, we have found that the re-folding co-chaperone, P23, may also regulate tau biology, acting rather to prevent its degradation. This interaction would provide new evidence that AD pathogenesis is due in part to the mis-folding of the inherently linear tau protein, an event perhaps precipitated by amyloid accretion. In addition, the unique family of small heat shock proteins may act in an entirely different way to promote tau degradation. Therefore, in the mentored phase of this award, I plan to develop my skills in the administration of genetic material to the murine brain, focusing on viral mediated delivery of shRNAs and genes of interest. A major focus of this phase will be the delivery of the Hsp27 by AAV to tau transgenic mice to determine the impact that this would have on tau pathology. In the latter phase of the award, we will investigate two novel pathways that regulate tau degradation;one mediated primarily by Hsp27 and the other mediated by the mature Hsp90 complex. We plan to further investigate the impact that the bifurcation of the Hsp90 pathway might have on AD pathogenesis, exploring how restorative co-chaperones might not only prevent tau degradation, but may also promote its aggregation. In addition, we plan to examine the role that amyloid may have in promoting tau dysfunction to either impair or facilitate its processing via the chaperone network, perhaps providing a novel mechanism of AD onset. PUBLIC DESCRIPTION Alzheimer's disease is the result of abnormal protein accumulation in the brain with the primary risk factor being age. Our goal is to identify ways in which these proteins accumulate and perhaps identify new drug targets for the treatment of Alzheimer's disease. Specifically, we intend to focus on the removal of the proteins once they have already started to accumulate in an effort to reverse the progression of the disease rather than prevent it.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Transition Award (R00)
Project #
5R00AG031291-04
Application #
7917362
Study Section
Special Emphasis Panel (NSS)
Program Officer
Miller, Marilyn
Project Start
2007-09-30
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2010
Total Cost
$293,716
Indirect Cost
Name
University of South Florida
Department
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Lee, Daniel C; Ruiz, Claudia R; Lebson, Lori et al. (2013) Aging enhances classical activation but mitigates alternative activation in the central nervous system. Neurobiol Aging 34:1610-20
Abisambra, Jose F; Jinwal, Umesh K; Blair, Laura J et al. (2013) Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci 33:9498-507
Abisambra, Jose; Jinwal, Umesh K; Miyata, Yoshinari et al. (2013) Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau. Biol Psychiatry 74:367-74
Jinwal, Umesh K; Akoury, Elias; Abisambra, Jose F et al. (2013) Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J 27:1450-9
Koren 3rd, John; Miyata, Yoshinari; Kiray, Janine et al. (2012) Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance. PLoS One 7:e35566
Miyata, Yoshinari; Rauch, Jennifer N; Jinwal, Umesh K et al. (2012) Cysteine reactivity distinguishes redox sensing by the heat-inducible and constitutive forms of heat shock protein 70. Chem Biol 19:1391-9
Abisambra, Jose F; Jinwal, Umesh K; Suntharalingam, Amirthaa et al. (2012) DnaJA1 antagonizes constitutive Hsp70-mediated stabilization of tau. J Mol Biol 421:653-61
Suntharalingam, Amirthaa; Abisambra, Jose F; O'Leary 3rd, John C et al. (2012) Glucose-regulated protein 94 triage of mutant myocilin through endoplasmic reticulum-associated degradation subverts a more efficient autophagic clearance mechanism. J Biol Chem 287:40661-9
Congdon, Erin E; Wu, Jessica W; Myeku, Natura et al. (2012) Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy 8:609-22
Jinwal, Umesh K; Abisambra, Jose F; Zhang, Juan et al. (2012) Cdc37/Hsp90 protein complex disruption triggers an autophagic clearance cascade for TDP-43 protein. J Biol Chem 287:24814-20

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