The microtubule associated protein, tau, is involved in regulating microtubule stability and axonal transport. When tau becomes hyperphosphorylated it can disassociate from the microtubules and start to aggregate. These tau aggregates are the hallmarks of many diseases known as tauopathies. The heat shock protein 90 kDa (Hsp90) chaperone network is highly involved in modulating client proteins, including tau. However, during aging and disease the Hsp90 chaperone network becomes highly imbalanced with some Hsp90/co-chaperone complexes increasing, while others are repressed. This imbalance in Hsp90/co-chaperone complexes could result in a worsening of tau pathology in Alzheimer’s disease. Hsp90 inhibition has been of interest as a potential therapeutic for tauopathies for many years. However, issues with toxicity and bioavailability have dampened enthusiasm for Hsp90 as a viable therapeutic target. Hsp90 co-chaperones are currently being investigated for as potential therapeutic targets for tauopathies, with the hope that targeting co-chaperones will lead to more specific targeting without toxicity. One co-chaperone that has the potential to become a therapeutic target for tauopathies is the activator of Hsp90 ATPase homolog 1 (Aha1). Aha1 is the only known stimulator of the ATPase of Hsp90, so targeting this particular co-chaperone could potentially mimic the effects of Hsp90 inhibition with more specificity. In this study we found that Aha1 enhanced Hsp90-mediated tau aggregation and increased insoluble tau accumulation in vitro. Additionally, a novel Aha1 inhibitor was able to reduce the formation of insoluble tau in vitro. We also investigated the effects of Aha1 overexpression in the rTg4510 mouse model, which is a tauopathy model that stably overexpresses the P301L mutation of tau. Overexpression of Aha1 in these mice increased the accumulation of insoluble and oligomeric tau. Furthermore, Aha1 overexpression led to cognitive deficits and neurotoxicity. Due to the effect of Aha1 overexpression on tau we wanted to investigate the effects of Aha1 knock-down in the rTg4510 mice. Incredibly, Aha1 knock-down led to reductions in pathological Gallyas silver positive tau tangles and was able to rescue neuronal loss. Overall, this work highlights Aha1 as an important regulator of tau pathology through Hsp90. The Hsp90/Aha1 complex could provide a novel therapeutic target for the treatment of tauopathies.

Thesis (doctoral)--Swedish University of Agricultural Sciences, 2001. / Abstract inserted. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 174-188).

The major chaperones identified in Escherichia coli that assist in protein folding include trigger factor (TF), DnaK/DnaJ/GrpE and GroEL/GroES systems. The main ATP-dependent proteases are ClpXP, ClpAP, HslUV, Lon, and FtsH. From detailed sequence analysis, we found that tig (gene for TF), clpX, and clpP genes co-localize next to each other in most examined bacteria. We hypothesized that TF and ClpXP are functionally associated. TF is a ribosome-associated folding chaperone whereas ClpXP is a degradation complex. ClpX serves as the regulatory ATPase that recognizes substrates, unfolds and translocates polypeptides into ClpP for degradation. I found that TF physically interacts with ClpX, and that they collaborate to enhance degradation of certain ClpXP substrates. It is estimated that TF enhances the degradation of about 2% of newly synthesized E. coli proteins. One of the ClpXP substrates with degradation enhanced by TF was λO, the λ phage replication protein. Furthermore, TF also enhanced the degradation of ribosome-stalled λO nascent chains. Experiments suggest that TF transfers ribosome-stalled λO to ClpX for degradation by ClpP, demonstrating the existence of co-translational protein degradation in E. coli. To understand ClpXP mechanism, we had previously proposed that the degraded peptides are released from ClpP through transient equatorial side pores. To further understand ClpP dynamics, we determined the structure of ClpP(Ala153Cys) in its oxidized state. The structure shows that each opposing pair of protomers is linked by a disulfide bond. Unexpectedly, this structure resembles the compact structures of Streptococcus pneumoniae, Mycobacterium tuberculosis, and Plasmodium falciparum ClpPs, rather than the extended states seen in previous E. coli ClpP structures. Normal mode analysis of ClpP structures suggested that the iii compact structure is a naturally sampled conformation of WT ClpP. My findings provide insights for understanding ClpP dynamics as well as reveal a novel association between ClpXP protease and TF folding chaperone.

Thesis (Ph.D.)--University of Wollongong, 2006. / Typescript. Includes bibliographical references: leaf 228-250.

Thesis (Ph.D.)--University of Wollongong, 2003. / Typescript. Includes bibliographical references: leaf 247-274.

Thesis (M. S.)--Biology, Georgia Institute of Technology, 2006. / Jung Choi, Committee Member ; Yury Chernoff, Committee Chair ; kirill.lobachev@biology.gatech.edu, Committee Member.

Thesis (Ph. D.)--University of Chicago, Committee on Neurobiology, December 2002. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph.D.)--McMaster University, 2003. / Advisor: V.S. Ananthanarayanan. Includes bibliographical references. Also available via World Wide Web.

Thesis (Ph. D.)--Drexel University, 2007. / Includes abstract and vita. Includes bibliographical references (leaves 108-115).