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. ? ? ?
| Jinwal, Umesh K; Trotter, Justin H; Abisambra, Jose F et al. (2011) The Hsp90 kinase co-chaperone Cdc37 regulates tau stability and phosphorylation dynamics. J Biol Chem 286:16976-83 |
| Jones, Jeffrey R; Lebar, Matthew D; Jinwal, Umesh K et al. (2011) The diarylheptanoid (+)-aR,11S-myricanol and two flavones from bayberry (Myrica cerifera) destabilize the microtubule-associated protein tau. J Nat Prod 74:38-44 |
| Evans, Christopher G; Jinwal, Umesh K; Makley, Leah N et al. (2011) Identification of dihydropyridines that reduce cellular tau levels. Chem Commun (Camb) 47:529-31 |
| Jinwal, Umesh K; Dickey, Chad A (2011) Cell-based assays for regulators of tau biology. Methods Mol Biol 670:93-108 |
| Rousaki, Aikaterini; Miyata, Yoshinari; Jinwal, Umesh K et al. (2011) Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones. J Mol Biol 411:614-32 |
| Jinwal, Umesh K; O'Leary 3rd, John C; Borysov, Sergiy I et al. (2010) Hsc70 rapidly engages tau after microtubule destabilization. J Biol Chem 285:16798-805 |
| Dickey, Chad; Kraft, Clara; Jinwal, Umesh et al. (2009) Aging analysis reveals slowed tau turnover and enhanced stress response in a mouse model of tauopathy. Am J Pathol 174:228-38 |
| Jinwal, Umesh K; Miyata, Yoshinari; Koren 3rd, John et al. (2009) Chemical manipulation of hsp70 ATPase activity regulates tau stability. J Neurosci 29:12079-88 |
| Dickey, Chad A; Koren, John; Zhang, Yong-Jie et al. (2008) Akt and CHIP coregulate tau degradation through coordinated interactions. Proc Natl Acad Sci U S A 105:3622-7 |
