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).
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).
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).
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).
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).
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).
The Hsp90 N-terminal domain inhibitor, EC102, was used to demonstrate degradation of hyperphosphorylated pathologically relevant tau in cells (Dickey et al., 2007a).
All of these chaperones assist in various ways to help fold, refold and degrade misfolded proteins.
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).
Hsp90 requires ATP to perform these functions including protein degradation, protein folding, prevention of protein aggregation, and protein modification (Echeverría et al., 2011).
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).
Hsp90 and Hop are both involved in the CMA system;
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).
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).
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.
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).
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).
Proteins can also be degraded by CMA; however, CMA activity also decreases with age (Cuervo and Dice, 2000a).
An interesting PPIase, CyP40, decreases in aging and is further repressed in AD (Table 1; Brehme et al., 2014).
For instance, CyP40, FKBP52, PP5, Hop, p23, and Aha1 are all repressed in the aged brain.
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).
Interestingly, one co-chaperone is significantly induced in the aged brain and that is FKBP51.
Another member of this family, protein phosphatase 5 (PP5), is repressed in aging.
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.
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).
Conversely, there are also studies showing decreased levels of Hsp90 in aged human brain samples.
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).
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.
However, Hsp90 regulates tau and other aggregating proteins in coordination with a diverse group of co-chaperones (Schopf et al., 2017).
Inhibition of the ATPase activity of Hsp90 has been shown to have positive outcomes in cell culture and animal models of tauopathy.
Previous studies have shown that Hsp90 inhibition decreased the levels of hyperphosphorylated and/or mutated tau species both in cells and mice.
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).
Interestingly, overexpression of Cdc37 preserves tau, and its suppression reduces tau (Jinwal et al., 2012).
FKBP52 interacts both physically and functionally with tau and promotes tau aggregation in vitro (Giustiniani et al., 2015; Meduri et al., 2016).
p23 has an opposing effect on Hsp90 compared to Aha1. p23 works by inhibiting the ATPase activity of Hsp90.
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).
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).
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).
A previous study found that when Hop was depleted using siRNA, there was an accumulation of tau (Jinwal et al., 2013).
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).
The folliculin-interacting protein 1 (FNIP1) is able to interact with Hsp90 as a co-chaperone in order to inhibit its ATPase activity.
One study found that FNIP1, in complex with FNIP2 and Hsp90, was able to stabilize the tumor suppressor folliculin (FLCN; Woodford et al., 2016).
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).
Studies have shown that PP5 is able to dephosphorylate tau at several phosphorylation sites connected to AD pathology (Gong et al., 2004).
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).
Acetylation of Hsp90 affects client protein interaction and also decreases binding of Hsp90 to ATP (Yu et al., 2002; Mollapour and Neckers, 2012).
S-nitrosylation, oxidation and ubiquitination also inhibit Hsp90 chaperone activity (Blank et al., 2003; Martínez-Ruiz et al., 2005; Chen et al., 2008).
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).
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.
Aha1 levels have been shown to increase with AD.
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).
Previous studies have also implicated Aha1 for a role in cystic fibrosis.
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).
In tauopathic mice, CHIP regulates the removal of tau species that have undergone abnormal phosphorylation and folding (Dickey et al., 2007b).
One study found that in Drosophila, impaired Tom34 gene function led to enhanced tau pathology (Ambegaokar and Jackson, 2011).
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).
PP5 activity has been shown to be repressed in AD (Table 1; Liu et al., 2005).
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.