Targeting Tau as a Treatment for Tauopathies
The accumulation of hyperphosphorylated tau causes the formation of neurofibrillary tangles, a pathological hallmark of tauopathies, a group of diseases which includes Alzheimer's disease, frontal temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, Pick's disease and corticobasal degeneration. Therapeutics aimed at eliminating hyperphosphorylated tau are thus of considerable interest. One promising approach to promote the clearance of hyperphosphorylated tau is via the manipulation of molecular chaperones, like Hsp90. Molecular chaperones function to refold misfolded proteins or to target them for proteasomal degradation.
Degradation of abnormal tau by Hsp90 inhibitors
We have shown that hyperphosphorylated tau is a client of the heat shock protein, Hsp90 [1, 2]. Hsp90 regulates the folding or degradation of its client proteins by forming multi-component complexes with other chaperones. The binding of nucleotides to Hsp90 alters its conformation and defines the subset of chaperones with which it interacts. When bound by ADP, Hsp90 associates with Hsp70/Hsp40 complexes bound to client proteins. This complex recruits ubiquitin ligases, like CHIP, to direct the client protein to proteasomes for degradation (Fig. 1). The replacement of ADP with ATP alters Hsp90 conformation, releasing Hsp70/Hsp40 and allowing the recruitment of another set of cochaperones, including p23 and cdc37. This complex folds and stabilizes the client protein now bound by Hsp90. Hsp90 can thus cycle between different multi-chaperone complexes: one complex favoring the refolding of abnormal proteins and the other targeting proteins for degradation. Hsp90 inhibitors (HSP90i) convert the Hsp90 complex from a catalyst for protein folding into one that induces protein degradation (Fig. 1). Thus, HSP90i have two functional consequences: 1) the degradation of Hsp90 and its bound client protein; and 2) the activation of heat shock factor 1 (HSF1), which is normally suppressed by Hsp90. HSF1 activation results in the transcription of stress-induced chaperones, like Hsp70.
Our findings indicated that HSP90i cause the preferential degradation of hyperphosphorylated tau in cultured cells and mice [1, 2], thereby highlighting the therapeutic potential of HSP90i for Alzheimer's disease and other tauopathies. Our studies are now geared towards determining if HSP90i, by enhancing the degradation of abnormally phosphorylated tau, provide protection against tau-induced neuronal loss and behavior deficits in rTg4510 mice, a model of 4R tauopathy. It is noteworthy that we have found that Hsp90 in affected areas of Alzheimer's disease brain is markedly more sensitive to Hsp90 inhibition than Hsp90 in unaffected areas, suggesting that HSP90i possess an exploitable therapeutic index . Currently, we are studying whether pathological tau underlies the heightened sensitivity of Hsp90 for HSP90i. Given that the binding affinity of Hsp90 for HSP90i is increased when Hsp90 is acetylated [3, 4], and given that tau has been reported to inhibit histone deacetylase 6 (HDAC6) , a cytosolic Hsp90 deacetylase, tau could indirectly increase the affinity of Hsp90 for HSP90i (Fig.1). Therefore, we are studying the interplay between tau and HDAC6 and whether HDAC6 regulates Hsp90-dependent degradation of tau.
Targeting heat shock protein complexes for the treatment of tauopathies
The fact that there exists cellular machinery capable of recognizing abnormally modified tau provides a powerful means for targeting only the tau that is harmful to neuronal health. That heat shock proteins recognize abnormal tau is particularly impressive, but heat shock proteins are also actively involved in antigen presentation through major histocompatibility complex molecules leading to a robust immune response. In fact, complexes formed between heat shock proteins and abnormal peptides that have been purified from affected individuals have a proven track record for providing immunity against a variety of viruses and cancers; most critically, the abnormal peptides do not have to be identified for this type of immunization. This, coupled with the finding that active immunization against phosphorylated tau peptides inhibits tau aggregation and slows the behavioral phenotype in at least one model of human 4R tauopathy , provides substantial impetus for these techniques to be combined in order to determine if heat shock protein-peptide complexes purified from rTg4510 mice are able to prevent or inhibit tau-induced neurodegeneration. Should this approach prove feasible, it could lead to a novel therapy for Alzheimer's disease and other tauopathies, as well as provide a means of treating the large variety of neurodegenerative diseases characterized by abnormal protein folding. Finally, the binding of heat shock proteins to abnormal tau species could expedite the identification of harmful tau products which, in turn, would help increase our understanding of the detrimental consequences of aberrant tau products as well as how such products are generated. As our knowledge regarding tau-induced toxicity expands, so too will the likelihood of developing effective therapies for tauopathies.
References cited on this page:
- Dickey, C.A., et al., The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest, 2007. 117(3): p. 648-58.
- Dickey, C.A., et al., HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. Faseb J, 2006. 20(6): p. 753-5.
- Rao, R., et al., HDAC6 inhibition enhances 17-AAG--mediated abrogation of hsp90 chaperone function in human leukemia cells. Blood, 2008. 112(5): p. 1886-93.
- Yang, Y., et al., Role of acetylation and extracellular location of heat shock protein 90alpha in tumor cell invasion. Cancer Res, 2008. 68(12): p. 4833-42.
- Perez, M., et al., Tau--an inhibitor of deacetylase HDAC6 function. J Neurochem, 2009. 109(6): p. 1756-66.
- Asuni, A.A., et al., Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci, 2007. 27(34): p. 9115-29.