PubMed: 29311797

Imbalances in the Hsp90 Chaperone Machinery: Implications for Tauopathies.
Frontiers in neuroscience
Blair LJ | Koren J 3rd | Shelton LB

Evidence 189b5ee73b

The Cdc37/Hsp90 inhibitors, Celasterol and Withaferin A (Zhang et al., 2008; Yu et al., 2010), reduce tau levels and a new compound, platycodin D has just been discovered (Li et al., 2017). Platycodin D does not affect the ATPase activity of Hsp90, but instead disrupts the interaction between Hsp90 and Cdc37 leading to client protein degradation without an increase in Hsp70 (Li et al., 2017).

Evidence fca38899f6

Another N-terminal Hsp90 ATPase inhibitor, 17- AAG, was shown to decrease levels of phosphorylated tau in cells, and a related N-terminal Hsp90 ATPase inhibitor, PU- DZ8, reduced soluble and insoluble tau in tauP301L mice (Luo et al., 2007).

Evidence 0fd222e118

Additionally, Aha1-specific inhibitors have been recently developed (Hall et al., 2014). One of these inhibitors, KU-177, reduced insoluble tauP301L levels in cells (Shelton et al., 2017).

Evidence 8b9f95708c

The pathological accumulation of tau is a hallmark in several neurodegenerative disorders collectively termed tauopathies (Kovacs, 2015); a series of diseases including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), Pick’s disease, and chronic traumatic encephalopathy (CTE; Guo et al., 2017).

Evidence 2aba584eca

While a direct role of XAP2 in tau pathogenesis has not been described, studies have shown that XAP2 is activated by histone deacetylase (HDAC) 6, which has been linked to pathogenic tau (Kekatpure et al., 2009; Cook et al., 2012; Selenica et al., 2014).

Evidence dceb76b440

In addition, XAP2 coordinates with Hsp90 to regulate glucocorticoid receptor signaling (Laenger et al., 2009), which has also been implicated in the production of pathogenic tau (Pinheiro et al., 2016).

Evidence 7e140e525a

The Hsp90 N-terminal domain inhibitor, EC102, was used to demonstrate degradation of hyperphosphorylated pathologically relevant tau in cells (Dickey et al., 2007a).

Evidence d70fa4f66c

All of these chaperones assist in various ways to help fold, refold and degrade misfolded proteins.

Evidence 97328dec39

Interestingly, one study demonstrated that patients chronically treated with FK506, which inhibits the PPIase domain of many of the FKBPs, significantly reduced the incidence of AD (Taglialatela et al., 2015).

Evidence 56278b7666

Hsp90 requires ATP to perform these functions including protein degradation, protein folding, prevention of protein aggregation, and protein modification (Echeverría et al., 2011).

Evidence 7b0778dfd9

Hsp90α is involved in growth promotion, cell cycle regulation, stress-induced cytoprotection, and cancer cell invasiveness; whereas Hsp90β is involved with early embryonic development, germ cell maturation, cytoskeletal stabilization, cellular transformation, signal transduction, and long-term cell adaptation (Eustace et al., 2004; Sreedhar et al., 2004).

Evidence 66a2cbafb9

Hsp90 and Hop are both involved in the CMA system;

Evidence 4dff91539d

Hsp90 is critical to maintaining proteostasis (Brehme et al., 2014) and accounts for up to 6% of all protein within the cell during times of stress (Picard, 2002; Prodromou, 2016).

Evidence 17b986888a

Aging is the biggest risk factor for developing a neurodegenerative disease, but the specific factors which cause these predominantly sporadic diseases are still under investigation (Reeve et al., 2014).

Evidence 7560c7f17d

Not only does aging lead to an increased likelihood of protein misfolding and aggregation, it is compounded by a decrease in the efficiency of the protein degradation machinery.

Evidence 86d9398ac3

The activity of both the proteasome, which is the main mechanism of protein degradation (Rock et al., 1994; Conconi et al., 1996), and chaperone-mediated autophagy (CMA; Cuervo and Dice, 2000b) is significantly impaired with aging and is especially pronounced in post-mitotic cells, such as neurons, potentially resulting in neurodegenerative disease (Terman, 2001).

Evidence f0b2a504cc

In addition to the problems faced with an overwhelmed chaperone network, the proteolytic activity of the proteasome also declines with aging, and in fact Hsp90 has been shown to protect the proteasome from age-related, oxidative-dependent decline (Conconi and Friguet, 1997).

Evidence c4c2101ffd

Proteins can also be degraded by CMA; however, CMA activity also decreases with age (Cuervo and Dice, 2000a).

Evidence 5b11833867

An interesting PPIase, CyP40, decreases in aging and is further repressed in AD (Table 1; Brehme et al., 2014).

Evidence aed4c9af7a

For instance, CyP40, FKBP52, PP5, Hop, p23, and Aha1 are all repressed in the aged brain.

Evidence c9b370d984

However, throughout aging, FKBP51 levels progressively increase and are further increased in AD brain samples (Table 1; Blair et al., 2013; Sabbagh et al., 2014).

Evidence 69a6a859d8

Interestingly, one co-chaperone is significantly induced in the aged brain and that is FKBP51.

Evidence 5e7d1497cf

Another member of this family, protein phosphatase 5 (PP5), is repressed in aging.

Evidence e32ce5e1a5

Since Aha1 levels are repressed in aging, but are abnormally preserved in AD, tau aggregation could be accelerated in part by Aha1 in the AD brain.

Evidence 7fab0d7424

One study focused on the basal levels of cytosolic Hsp90 in peripheral blood mononuclear cells (PBMC) and found that in aged human samples there was an increase in Hsp90 under normal physiological conditions when compared to young samples (Njemini et al., 2007).

Evidence fef53adf1a

Conversely, there are also studies showing decreased levels of Hsp90 in aged human brain samples.

Evidence c8aad96166

One study found that cytosolic Hsp90 was repressed in the superior frontal gyrus, while another demonstrated a similar repression in the prefrontal cortex of aged patients compared to controls (Berchtold et al., 2008; Loerch et al., 2008; Brehme et al., 2014).

Evidence f3418d28a1

These PTMs increase with aging and can alter the ability of Hsp90 to function properly as well as change the ability of different co-chaperones to bind.

Evidence 900cf62efa

However, Hsp90 regulates tau and other aggregating proteins in coordination with a diverse group of co-chaperones (Schopf et al., 2017).

Evidence 4ffe9c7fb0

Inhibition of the ATPase activity of Hsp90 has been shown to have positive outcomes in cell culture and animal models of tauopathy.

Evidence 98cf9dee37

Previous studies have shown that Hsp90 inhibition decreased the levels of hyperphosphorylated and/or mutated tau species both in cells and mice.

Evidence f4083f0f90

Cdc37 is also required for the stable folding of protein kinases in coordination with Hsp90 (Calderwood, 2015). Many of these kinases are known to phosphorylate tau at sites associated with AD, such as GSK3β and MAPK13 (Taipale et al., 2012; Jin et al., 2016).

Evidence dbb0d424e8

Interestingly, overexpression of Cdc37 preserves tau, and its suppression reduces tau (Jinwal et al., 2012).

Evidence f12c669125

FKBP52 interacts both physically and functionally with tau and promotes tau aggregation in vitro (Giustiniani et al., 2015; Meduri et al., 2016).

Evidence 727ac12441

p23 has an opposing effect on Hsp90 compared to Aha1. p23 works by inhibiting the ATPase activity of Hsp90.

Evidence 6d838f080d

As a co-chaperone, p23 works to suppress protein aggregation and exhibits chaperoning activity, although p23 is not able to refold proteins on its own (Freeman et al., 1996).

Evidence 908a8e1608

Inhibition of p23 in an siRNA screen of Hsp90 co-chaperones showed that silencing p23 reduced both total and phospho-tau (Jinwal et al., 2012, 2013).

Evidence bba1a77b09

p23 also plays an important role in preventing endoplasmic reticulum (ER) stress-induced cell death, which can be triggered by misfolded proteins, like tau (Rao et al., 2006; Abisambra et al., 2013).

Evidence 01b486fc26

A previous study found that when Hop was depleted using siRNA, there was an accumulation of tau (Jinwal et al., 2013).

Evidence 0a46050163

Contrary to the neuroprotective effects of CyP40, two FK506- binding proteins (FKBPs) have been shown to stimulate toxic tau aggregation (Blair et al., 2013; Giustiniani et al., 2015; Kamah et al., 2016). One of these, FKBP51, coordinates with Hsp90 to preserve toxic tau oligomers in vivo (Blair et al., 2013).

Evidence 31940e657c

The folliculin-interacting protein 1 (FNIP1) is able to interact with Hsp90 as a co-chaperone in order to inhibit its ATPase activity.

Evidence abb57b3a54

One study found that FNIP1, in complex with FNIP2 and Hsp90, was able to stabilize the tumor suppressor folliculin (FLCN; Woodford et al., 2016).

Evidence 40c0231ba2

CyP40 was recently shown to disaggregate tau fibrils in vitro and prevents toxic tau accumulation in vivo preserving memory, demonstrating a neuroprotective role for CyP40 in the brain (Baker et al., 2017).

Evidence ff67f261d3

Studies have shown that PP5 is able to dephosphorylate tau at several phosphorylation sites connected to AD pathology (Gong et al., 2004).

Evidence a041bcd90a

This study found that reductions in S100A1 also led to massive reductions in both phospho- and total tau levels in cells (Jinwal et al., 2013).

Evidence bd8a15d9f5

Acetylation of Hsp90 affects client protein interaction and also decreases binding of Hsp90 to ATP (Yu et al., 2002; Mollapour and Neckers, 2012).

Evidence a231918b5f

S-nitrosylation, oxidation and ubiquitination also inhibit Hsp90 chaperone activity (Blank et al., 2003; Martínez-Ruiz et al., 2005; Chen et al., 2008).

Evidence f13bf2aeca

Phosphorylation of Hsp90 leads to reduced chaperoning ability and phosphorylation of specific tyrosine residues can affect the ability of Hsp90 to interact with distinct client proteins (Zhao et al., 2001; Mollapour and Neckers, 2012).

Evidence e9b978f392

The activator of Hsp90 ATPase homolog 1 (Aha1) works as a co- chaperone to stimulate the ATPase function of Hsp90 to regulate the folding and activation of client proteins.

Evidence 57bdf635d6

Aha1 levels have been shown to increase with AD.

Evidence f770baeeb8

In the same study, we found that high levels of Aha1 in a tau transgenic mouse model increased tau oligomers as well as neuronal loss concomitant with cognitive deficits (Shelton et al., 2017).

Evidence 54bc8e54c7

Previous studies have also implicated Aha1 for a role in cystic fibrosis.

Evidence a5ebc80d0e

CHIP has been linked to several neurodegenerative disorders including Huntington’s disease, Parkinson’s disease and AD as well as other diseases such as cystic fibrosis and cancer (Dickey et al., 2007b; Edkins, 2015).

Evidence f104223e46

In tauopathic mice, CHIP regulates the removal of tau species that have undergone abnormal phosphorylation and folding (Dickey et al., 2007b).

Evidence d789293948

One study found that in Drosophila, impaired Tom34 gene function led to enhanced tau pathology (Ambegaokar and Jackson, 2011).

Evidence 3d8684c166

However, it is interesting to note that FKBP52 levels are lower in the cortex of AD patients’ brains (Table 1; Brehme et al., 2014; Meduri et al., 2016).

Evidence 0d2c90057c

PP5 activity has been shown to be repressed in AD (Table 1; Liu et al., 2005).


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