PubMed: 21882945

Molecular chaperones and regulation of tau quality control: strategies for drug discovery in tauopathies.
Future medicinal chemistry
Dickey CA | Gestwicki JE | Kiray J | Koren J | Miyata Y

Evidence 690dfd5ee0

For example, Hsp90 inhibitors cause degradation of tau and many cancer-related substrates [85].

Evidence a6f63caaa0

Moreover, these compounds were found to prolong binding of Hsp90 to a model substrate, which was sufficient to promote its degradation [142]

Evidence 991362f634

There are no cures for any tauopathy. Neuroprotective agents, such as acetylcholinesterase inhibitors and NMDA antagonists, have been approved for use in the clinic, based on their ability to slow the rate of cognitive decline in patients with moderate to severe AD (reviewed in [36])

Evidence ae9b4aac69

Furthermore, recent evidence suggests that tau is essential for the neurotoxicity of amyloid-b, providing a possible link between these classic AD targets and suggesting that reductions in tau levels might be important via multiple, beneficial mechanisms [46–48]

Evidence 900802c7e4

As might be expected given the diverse mechanisms of these compounds, known Hsp70 inhibitors represent a variety of chemical classes, including dihydropyrimidines, adenosine analogs, polyamines and others (Figure 1) [52,63]. Moreover, many of these inhibitors, including methylene blue and MKT-077, have poorly understood mechanisms

Evidence 6c1e8e906d

These efforts have produced early-stage molecules of multiple different chemical classes, including rhodanine-based inhibitors, phenylthiazolylhydrazides, N-phenylamines, anthraquinones, benzothiazoles, phenothiazines and polyphenols [41]

Evidence bb1815f0e4

More recently, there has also been interest in developing compounds, such as celastrol (Figure 1), that selectively disrupt association of co-chaperones with Hsp90 as an alternative way to control chaperone activity [93–96].

Evidence f1ee94dded

Work on Hsp90 inhibitors benefited from the early discovery of the natural product, geldanamycin, which competes with ATP and induces destabilization of Hsp90-bound proteins [87]

Evidence cc300e6321

For example, the Hsp90 inhibitor geldanamycin mimics ADP binding, but also inhibits recruitment of p23, which is a necessary step in client maturation [145].

Evidence 9b9d3f6718

Since this discovery, a number of high-affinity analogs, such as 17-AAG, and alternative synthetic scaffolds, including radicicol and PU-H71, have been reported (Figure 1) [85,88]. These compounds bind in either the N-terminal ATP-binding site (e.g., 17-AAG, radicicol and PU-H71) [89] or C-terminal dimerization domain (e.g., novobiocin and A4) [90,91], and they show great promise as both anticancer compounds and research tools for understanding Hsp90 biology

Evidence 8ea295e6c6

Using high-throughput screening against the J-protein-stimulated ATPase activity of an Hsp70, we also found polyphenols that selectively block J-stimulated activities by interfering with J-protein recruitment to the Hsp70 complex [72].

Evidence 744f8b5544

However, this issue is more complicated, as other work has shown that chemical inhibition of Hsp90 by 17-AAG and other inhibitors reduces cellular levels of two phospho- tau species, pS202/T205 and pS396/S404, both of which are relevant to AD pathogenesis [119].

Evidence 87c9d02b89

Tauopathies are a family of neurodegenerative disorders characterized by the appearance of aggregates of the microtubule-associating protein, tau.

Evidence 423eb8d6ef

The intrinsic ATPase activity of Hsp70 is very weak (~0.2 nmol/μg/min) [60] and, under physiological conditions, it is regulated by cochaperones, including J-proteins and nucleotide exchange factors (NEFs).

Evidence 328403d096

Briefly, J-proteins cause a conformational change in Hsp70s that accelerates ATP hydrolysis [61], while NEFs facilitate ADP release [62]

Evidence 2027353b30

Importantly, the Hsps are also critical at the end of a protein’s life, as they facilitate turnover by the proteasome system and the clearance of proteotoxic aggregates by autophagy [53]

Evidence 0d1b881b54

Molecular chaperones are abundant and highly conserved proteins that assume an important role in protein quality control

Evidence bd3ea876a5

For example, we found that dihydropyrimidine-based molecules can either force the association of a prokaryotic Hsp70 with its J-protein partner or, with a relatively modest change in chemical structure, related compounds could block this contact [73].

Evidence 874cba085e

For example, VER-155008 is an ATP-competitive compound developed by structure-guided design [69,70]

Evidence 93dd66d89b

Several members of the chaperone family are upregulated in response to stress and, thus, these factors have been termed heat shock proteins (Hsps)

Evidence dc3a8e3981

These proteins are ATP-independent chaperones that undergo homo-oligomerization in response to stress [97,98]

Evidence 0f515ca566

Recently, our group demonstrated that viral delivery of wild-type Hsp27 into the brains of tau-transgenic mice reduced tau levels and rescued long-term potentiation deficits.

Evidence 6e926748b1

For example, tau pathology closely correlates to neuron loss and cognitive deficits

Evidence a952cdf6dc

Interestingly, tau clearance is known to be impaired in the aging brain [45], supporting the idea that diminished quality control might be conducive to certain tauopathies, such as AD, which are linked to aging

Evidence 13de5c61d9

In relation to tau biology, FKBP51 enhances the association of Hsp90 with tau, co-localizes with tau in murine neurons, coimmunoprecipitates with tau in AD tissue samples and increases with age in an AD mouse model [136].

Evidence f13fca7979

To allow substrate release, Hsp27 oligomerization is reversible; a process that is regulated, at least in part, by phosphorylation

Evidence 8832cdb822

All proteins, including tau, are subject to extensive regulation by the cellular quality control pathways, which carefully control the balance between protein expression and turnover to maintain healthy protein homeostasis (or proteostasis)

Evidence c87d3ae12c

Alternatively, either Hsp70 or Hsp90 can recruit the ubiquitin E3 ligase, C-terminal Hsp70 interacting protein (CHIP), to degrade the bound substrate [104]

Evidence 4dfdbdaee1

For example, BAG-2 inhibits client ubiquitination by CHIP by interfering with the interaction between CHIP and E2 ubiquitin-conjugating enzymes [148].

Evidence c3b738482a

In general, phosphorylation of tau reduces its affinity for microtubules [30], while dephosphorylation via enzymes such as PP2A and PP5 restores binding

Evidence fe92ce01ca

Interestingly, it was recently found that reducing the levels of Akt, another client of the Hsp90/CHIP complex, facilitates tau degradation [123], suggesting a synchronized balance between competing Hsp90 substrates that may be driven, in part, by their relative abundance or susceptibility to Hsp90 binding

Evidence 6cfa8cdd75

During protein quality control, Hsp70, Hsp90 and Hsp27 (and their co-chaperones) often work in concert. If prolonged misfolding is detected, the chaperones shuttle the protein to a degradation endpoint, such as the proteasome or autophagy

Evidence ec6e3ded56

Hsp27 has emerged as a potential target for tau regulation based on early findings that it preferentially binds to phosphorylated and hyperphosphorylated tau and promotes their clearance [125,126]

Evidence c223ab4ca4

However, astrocyte-derived Hsp27 has been shown to promote tau accumulation and Hsp27 associates with tau tangles in a mouse model [127,128], suggesting a more complex relationship

Evidence 6993ef2217

Although both Hsp70 and Hsp90 can promote degradation of client proteins, it has recently been shown that, functionally, the Hsp70 complex often dominates triage decisions [85,107,109]

Evidence d815004054

Hsp90 was also shown to increase association of tau with microtubules [114]; however, its binding is not well characterized and it is not known whether this is a direct or indirect process

Evidence 8c5ae11df7

For example, it has recently been shown that Hsp90 promotes tau’s phosphorylation by its ability to stabilize GSK3b [118]

Evidence 5c018d363d

Together, multiple studies suggest that Hsp90 regulates the stability of both phospho- and mutant-tau

Evidence 9863a722f0

Finally, the FKBP51–Hsp90 complex has been proposed to be responsible for the interaction of tau with phosphatases, helping to restore binding to microtubules [137].

Evidence 579bf11044

In this model,accumulation of an Hsp70–substrate complex (either via treatment with chemical inhibitors or because of intrinsic properties of the substrate) might allow enough time for a degradation factor (e.g., CHIP) to bind and facilitate polyubiquitination.

Evidence 0872392068

Hsp70 has been shown to both stabilize binding of tau to microtubules [114] and promote its degradation in combination with CHIP [115,116]

Evidence 29b9f148a1

In fact, recent work from our group has shown that inhibition of the ATPase activity of Hsp70/Hsc70 promotes proteasomal degradation of tau; whereas activation results in tau accumulation [117]

Evidence 25871921b7

The fact that Hsp70 inhibitors reduce tau levels without affecting other likely Hsp70 substrates, such as a-synuclein or TDP-43, generally supports the idea that substrates are actively involved in dictating their own fate [117]

Evidence c3c0ef9a97

Recent structural studies have suggested that Hsp90 functions as a homodimer in which the C-terminal domains of two Hsp90 molecules are in contact at the bottom of the ‘V-shaped’ open conformer

Evidence 387e8a7166

This model is consistent with the data that hyperphosphorylated tau appears to be specifically selected for degradation by some chaperone machines, such as the Hsp90–FKBP51 complex, without effects on normal tau [132,136].

Evidence a0f2f517aa

Recently, the co-chaperone FK506-binding protein 51 kDa (FKBP51) has been implicated as a modulator of tau binding to microtubules

Evidence c96ad8927a

These interactions may be functionally important because silencing FKBP51 reduces tau and phosphorylated-tau levels [136].

Evidence 5e07ce47d2

For example, the co-chaperones cdc37, a peptidyl-prolyl cis-trans isomerase (PPIase) family member, and p23 are all critical for the transfer of kinases to Hsp90 and maturation of the active protein [76,105]

Evidence 012f99d38f

In another example, McClellan et al. showed that von Hippel–Lindau tumor-suppressor protein requires Hsp70 for its folding and degradation, whereas Hsp90 is only required for degradation [149].

Evidence c7e48da068

BAG1 is upregulated in the hippocampus of AD patients [130], where it associates with tau and increases tau levels in cooperation with Hsp70 [131]

Evidence b22c3913fa

BAG1 silencing decreases tau levels, consistent with a critical role for this co-chaperone in protecting tau from degradation.

Evidence d481fb9161

However, another related BAG family member, BAG2, interacts with Hsp70 and tau but, unlike BAG1, assists clearance of phosphorylated tau [132]

Evidence 91b6353c91

However, hyperphosphorylated forms of tau are more prone to aggregate, which might decrease their solubility and remove them from normal cycling

Evidence eceaa6b247

Phosphorylation of tau by the kinases GSK3b, Cdk5 and MARK2 is a major regulator of its microtubule interactions

Evidence abec0e9634

HOP was also required for degradation, indicating that transfer of von Hippel–Lindau from the Hsp70 complex to Hsp90 is a necessary part of its degradation pathway.

Evidence a1ad835cda

As in the case of Hsp70, cochaperones of Hsp90, such as Aha1, cdc37 and TPR domain-containing proteins, regulate its ATPase activity and control its conformational transitions (reviewed in [84]).

Evidence f6031e78f1

In addition, Hsp90’s hydrolysis of ATP, which is stimulated by Aha1, facilitates polypeptide release [82,106] and transfer to CHIP or other E3 ligases [107,108]

Evidence b141058128

Importantly, MARK2-based phosphorylation of tau is accelerated by the priming activity of either Cdk5 or GSK3b [29], suggesting that tau phosphorylation involves a series of ordered kinase events.

Evidence 9a415bc593

The expression of Hsps is regulated by heat shock factor 1 (HSF1), which, under stress conditions, becomes associated with heat shock elements to elevate the transcription of Hsps and other proteins [51].

Evidence 3aa946d2ac

However, the mechanisms that link HSF1 induction to improved proteostasis are not yet clear

Evidence 410faaf6ca

In addition, recent work has demonstrated that Hsc70, the constitutive cytosolic form of Hsp70s, also dynamically regulates the association of tau with microtubules

Evidence a9e6767ff6

This co-chaperone is of interest in tauopathies because Hsp110 knockout mice show an age-dependent accumulation of phosphorylated tau in the hippocampus [135].

Evidence 22d96b4bee

However, under potentially proteotoxic conditions, the post-translational modifications or mutations that damage tau’s affinity for microtubules and favor its aggregation are thought to generate a molecular ‘danger signal’ that specifically alerts the quality control system [112,113].


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