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Luo W, Dou F, Rodina A, Chip S, Kim J, Zhao Q, Moulick K, Aguirre J, Wu N, Greengard P, Chiosis G. Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc Natl Acad Sci U S A. 2007 May 29;104(22):9511-6. PubMed.
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Mayo Clinic College of Medicine
Chaperones are molecular machines designed to maintain proteins in a properly folded state (1). Misfolded or misassembled proteins that cannot be corrected by chaperones are ubiquitinated and thereby targeted for degradation by the proteasome (2). We and others proposed that the chaperone and proteasome systems may act in concert in clearing the toxic forms of phosphorylated tau (p-tau) that are associated with tauopathies, particularly Alzheimer disease (3-5). This same approach might also work for other neurodegenerative diseases.
Hsp90 inhibitors bind to the ATPase domain of Hsp90, which prevents any further attempts at refolding the client proteins, instead promoting their proteasomal degradation. Recently, we were the first to demonstrate that pharmacologic manipulation of Hsp90 activity through the use of Hsp90 inhibitors was able to selectively reduce “abnormal” p-tau species in cultured cells (3,6) and in mice (4). We identified EC102 as an Hsp90 inhibitor with the optimal properties to facilitate blood-brain barrier permeability. Once-daily peripheral administration of this compound into transgenic tau mice for one week significantly and specifically reduced only abnormal tau species in the brains of these mice, preserving “normal” tau. In cell culture, we described a mechanism whereby knocking down Hsp90 with siRNA abolished the EC102 effect, indicating that Hsp90 is required as a structural component of a tau-refolding/degradation complex and therefore a "client" of Hsp90. We also highlight the role of the tau ubiquitin ligase CHIP as critical for this process, consistent with our previous findings in CHIP null mice (7). Most remarkable was our finding that the Hsp90 complex isolated from only those areas of the AD brain that accumulate amyloid and tau had a 1,000-fold higher affinity for Hsp90 inhibitors. Unaffected regions from these same patients as well as control brains did not have this high affinity complex. These results suggest that Hsp90 antagonists might selectively target areas of injury and act like a "magic bullet" for treatment of Alzheimer disease.
The most recent contribution to the area of Hsp90 inhibitor therapy for Alzheimer disease from Gabriela Chiosis’ group largely confirms these data. Their work strengthens the notion that Hsp90 inhibitors can preferentially degrade only abnormal tau species, the production of which is certainly enhanced by mutations in tau. They also describe the efficacy of these drugs over a relatively short dosing period in two distinct mouse models of tauopathy; the same hTau model used in our previous work, that overexpresses all six isoforms of wild-type human tau, and the JNPL3 mouse model that overexpresses a single human tau isoform harboring the P301L mutation that causes FTDP-17, a heritable form of amyloid-negative tauopathy. They also suggest that tau exists in a complex with Hsp90 and p35, a component of the Cdk5 complex which is known to aberrantly phosphorylate tau; however, this complex seems to predominate in CNS regions that lack tau pathology in the JNPL3 model.
Collectively, these studies provide the foundation for future investigation of these compounds to treat Alzheimer disease, using alternative transgenic mouse models. Specifically, determining whether Hsp90 inhibition can delay the pathological progression and memory loss in an inducible mouse model of tauopathy (rTg4510) will establish the framework for introduction to the clinic. With the recent advance in the field demonstrating that an amyloid-depositing mouse model does not develop memory deficits on a tau knockout background (8), it is clear that tau has finally emerged as a legitimate target for AD therapeutics.
References:
Dickey CA, Petrucelli L. Current strategies for the treatment of Alzheimer's disease and other tauopathies. Expert Opin Ther Targets. 2006 Oct;10(5):665-76. PubMed.
Ciechanover A. The ubiquitin-proteasome proteolytic pathway. Cell. 1994 Oct 7;79(1):13-21. PubMed.
Dickey CA, Dunmore J, Lu B, Wang JW, Lee WC, Kamal A, Burrows F, Eckman C, Hutton M, Petrucelli L. HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. FASEB J. 2006 Apr;20(6):753-5. PubMed.
Dickey CA, Kamal A, Lundgren K, Klosak N, Bailey RM, Dunmore J, Ash P, Shoraka S, Zlatkovic J, Eckman CB, Patterson C, Dickson DW, Nahman NS, Hutton M, Burrows F, Petrucelli L. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest. 2007 Mar;117(3):648-58. PubMed.
Dou F, Netzer WJ, Tanemura K, Li F, Hartl FU, Takashima A, Gouras GK, Greengard P, Xu H. Chaperones increase association of tau protein with microtubules. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):721-6. PubMed.
Dickey CA, Eriksen J, Kamal A, Burrows F, Kasibhatla S, Eckman CB, Hutton M, Petrucelli L. Development of a high throughput drug screening assay for the detection of changes in tau levels -- proof of concept with HSP90 inhibitors. Curr Alzheimer Res. 2005 Apr;2(2):231-8. PubMed.
Dickey CA, Yue M, Lin WL, Dickson DW, Dunmore JH, Lee WC, Zehr C, West G, Cao S, Clark AM, Caldwell GA, Caldwell KA, Eckman C, Patterson C, Hutton M, Petrucelli L. Deletion of the ubiquitin ligase CHIP leads to the accumulation, but not the aggregation, of both endogenous phospho- and caspase-3-cleaved tau species. J Neurosci. 2006 Jun 28;26(26):6985-96. PubMed.
Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.
Laboratory for Alzheimer Disease
In this paper, Luo and colleagues showed that PU24FCI inhibited Hsp90 activity and accelerated tau degradation. It is quite surprising that this drug treatment in JNPL3 mice reduced the amount of sarcosyl-insoluble tau within hours. This result suggests the possibility that the drug treatment can resolve pre-existing PHF-tau aggregates through enhancing tau degradation.
Santacruz and colleagues showed previously that after turning off mutant tau expression, NFT formation continued while memory impairment and neuron loss were rescued (SantaCruz et al., 2005). These older results suggest that before but not during NFT formation, tau may be modified to affect neuronal function. Because PU24FCI treatment reduced both soluble and insoluble tau levels, Hsp90 may recognize a modified form of tau, which may be toxic, and reduce its level. If so, I wonder if PU24FCI treatment can prevent the severe motor dysfunction that is known to develop in the JNPL3 mouse strain?
References:
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005 Jul 15;309(5733):476-81. PubMed.
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