Imbalances in the Hsp90 Chaperone Machinery: Implications for Tauopathies

Abstract

The ATP-dependent 90 kDa heat shock protein, Hsp90, is a major regulator of protein triage, from assisting in nascent protein folding to refolding or degrading aberrant proteins. Tau, a microtubule associated protein, aberrantly accumulates in Alzheimer's disease (AD) and other neurodegenerative diseases, deemed tauopathies. Hsp90 binds to and regulates tau fate in coordination with a diverse group of co-chaperones. Imbalances in chaperone levels and activity, as found in the aging brain, can contribute to disease onset and progression. For example, the levels of the Hsp90 co-chaperone, FK506-binding protein 51 kDa (FKBP51), progressively increase with age. In vitro and in vivo tau models demonstrated that FKBP51 synergizes with Hsp90 to increase neurotoxic tau oligomer production. Inversely, protein phosphatase 5 (PP5), which dephosphorylates tau to restore microtubule-binding function, is repressed with aging and activity is further repressed in AD. Similarly, levels of cyclophilin 40 (CyP40) are reduced in the aged brain and further repressed in AD. Interestingly, CyP40 was shown to breakup tau aggregates in vitro and prevent tau-induced neurotoxicity in vivo. Moreover, the only known stimulator of Hsp90 ATPase activity, Aha1, increases tau aggregation and toxicity. While the levels of Aha1 are not significantly altered with aging, increased levels have been found in AD brains. Overall, these changes in the Hsp90 heterocomplex could drive tau deposition and neurotoxicity. While the relationship of tau and Hsp90 in coordination with these co-chaperones is still under investigation, it is clear that imbalances in these proteins with aging can contribute to disease onset and progression. This review highlights the current understanding of how the Hsp90 family of molecular chaperones regulates tau or other misfolded proteins in neurodegenerative diseases with a particular emphasis on the impact of aging.

The proteostasis network provides targets for neurodegeneration

“…Inhibition or knockdown of both of these HSP90 cofactors has been shown to reduce levels of tau aggregation, with effects which may be more specific and less toxic than the effects of HSP90 inhibition (Blair et al, ; Shelton et al, ). A number of small molecules have been reported to attenuate the Aha1–HSP90 interaction; KU‐177 [7] , a truncated derivative of the natural product noviobiocin, a C‐terminal domain inhibitor of HSP90, was reported to reduce tau aggregation through inhibition of the Aha1–HSP90 protein–protein interaction (Shelton et al, ). Stiegler et al reported Ham‐1 [8] —an apparent allosteric inhibitor of HSP90—that abolished Aha1‐mediated stimulation of HSP90 ATPase activity but did not significantly decrease native HSP90 ATPase activity nor dissociate the protein complex (Stiegler et al, ).…”

Management of Hsp90-Dependent Protein Folding by Small Molecule Targeting the Aha1 Co-Chaperone

“…This latter effect is a hallmark of a series of neurodegenerative diseases termed tauopathies, the most prominent of which is Alzheimer's disease (AD), where p-tau aggregates can be found in neurofibrillary tangles, senile plaques and cellular processes [87][88][89][90][91] . p-tau aggregates have been shown to be sensitive to the protective action of the heat shock protein molecular chaperone system 91 .…”

“…p-tau aggregates have been shown to be sensitive to the protective action of the heat shock protein molecular chaperone system 91 . Recent evidence has demonstrated that small molecules inhibitors of both Hsp70 and Hsp90, or modulation of the expression of regulatory co-chaperones, can mediate the clearance of p-tau in cells [87][88][89][90][91][92][93][94][95][96][97] .…”

“…Hsp90 is critical for the biogenesis and functional cycling of numerous clients proteins in addition to SHR (https://www.picard.ch/Hsp90Int/index.php) 5,113,114 , with microtubule associated protein, tau, being one of the best characterized [87][88][89][90][91]115 . Small molecule inhibitors of Hsp90 have emerged as potential therapeutic options for the treatment of tauopathies 87,89,90,116 .…”

Fibril formation rewires interactome of the Alzheimer protein Tau by π-stacking

“…Hsp70 can disaggregate Tau fibrils, while Hsp90 buffers aggregation prone stretches of Tau (Ferrari et al, 2018;Karagöz et al, 2014;Pratt et al, 2015). Hsp90 decreased efficiency during aging may contribute to Tau aggregation, which in turn may dictate further collapse of chaperones activity (Shelton et al, 2017).…”