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PubMed: 29311797

Title
Imbalances in the Hsp90 Chaperone Machinery: Implications for Tauopathies.
Journal
Frontiers in neuroscience
Volume
11
Issue
None
Pages
724
Date
2017-01-01
Authors
Blair LJ | Koren J 3rd | Shelton LB

Evidence 189b5ee73b
JSON

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).

a(CHEBI:"withaferin A") decreases act(p(FPLX:HSP90)) View Subject | View Object

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a(CHEBI:"withaferin A") decreases p(HGNC:MAPT) View Subject | View Object

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a(CHEBI:celastrol) decreases act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

a(CHEBI:celastrol) decreases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

a(PUBCHEM:162859) decreases complex(p(FPLX:HSP90), p(HGNC:CDC37)) View Subject | View Object

Appears in Networks:

Evidence fca38899f6
JSON

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).

a(CHEBI:tanespimycin) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

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a(CHEBI:tanespimycin) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

a(PUBCHEM:14719853) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

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a(PUBCHEM:14719853) decreases p(HGNC:MAPT) View Subject | View Object

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Evidence 0fd222e118
JSON

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).

a(HBP:"KU-177") decreases p(HGNC:MAPT, var("p.Pro301Leu")) View Subject | View Object

Appears in Networks:

Evidence 8b9f95708c
JSON

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).

a(HBP:"Tau aggregates") increases path(MESH:Tauopathies) View Subject | View Object

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Evidence 2aba584eca
JSON

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).

a(HBP:"Tau aggregates") association p(HGNC:HDAC6) View Subject | View Object

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MeSH
Cerebral Cortex

p(HGNC:HDAC6) increases act(p(HGNC:AIP)) View Subject | View Object

Appears in Networks:
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MeSH
Cerebral Cortex

p(HGNC:HDAC6) association a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence dceb76b440
JSON

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).

a(HBP:"Tau aggregates") association bp(GO:"glucocorticoid receptor signaling pathway") View Subject | View Object

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MeSH
Cerebral Cortex

bp(GO:"glucocorticoid receptor signaling pathway") association a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

complex(p(FPLX:HSP90), p(HGNC:AIP)) regulates bp(GO:"glucocorticoid receptor signaling pathway") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence 7e140e525a
JSON

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

a(HBP:EC102) increases deg(p(HGNC:MAPT, pmod(HBP:hyperphosphorylation))) View Subject | View Object

Appears in Networks:

Evidence d70fa4f66c
JSON

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

a(MESH:"Molecular Chaperones") association bp(GO:"protein folding") View Subject | View Object

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a(MESH:"Molecular Chaperones") association bp(MESH:Proteolysis) View Subject | View Object

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bp(GO:"protein folding") association a(MESH:"Molecular Chaperones") View Subject | View Object

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bp(MESH:Proteolysis) association a(MESH:"Molecular Chaperones") View Subject | View Object

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Evidence 97328dec39
JSON

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).

a(PUBCHEM:4456430) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence 56278b7666
JSON

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

bp(GO:"ATP metabolic process") increases act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

act(p(FPLX:HSP90)) increases bp(MESH:Proteolysis) View Subject | View Object

Appears in Networks:

act(p(FPLX:HSP90)) increases bp(GO:"protein folding") View Subject | View Object

Appears in Networks:

act(p(FPLX:HSP90)) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Appears in Networks:

act(p(FPLX:HSP90)) increases bp(GO:"protein modification process") View Subject | View Object

Appears in Networks:

Evidence 7b0778dfd9
JSON

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).

bp(GO:"adaptation of signaling pathway") association p(HGNC:HSP90AB1) View Subject | View Object

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bp(GO:"cell maturation") association p(HGNC:HSP90AB1) View Subject | View Object

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Annotations
MeSH
Germ Cells

bp(GO:"cytoskeleton organization") association p(HGNC:HSP90AB1) View Subject | View Object

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bp(GO:"embryo development") association p(HGNC:HSP90AB1) View Subject | View Object

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bp(GO:"regulation of cell cycle") association p(HGNC:HSP90AA1) View Subject | View Object

Appears in Networks:

bp(GO:"signal transduction") association p(HGNC:HSP90AB1) View Subject | View Object

Appears in Networks:

bp(GO:growth) association p(HGNC:HSP90AA1) View Subject | View Object

Appears in Networks:

bp(MESH:Cytoprotection) association p(HGNC:HSP90AA1) View Subject | View Object

Appears in Networks:

p(HGNC:HSP90AA1) association bp(GO:growth) View Subject | View Object

Appears in Networks:

p(HGNC:HSP90AA1) association bp(GO:"regulation of cell cycle") View Subject | View Object

Appears in Networks:

p(HGNC:HSP90AA1) association bp(MESH:Cytoprotection) View Subject | View Object

Appears in Networks:

p(HGNC:HSP90AA1) association path(MESH:"Neoplasm Metastasis") View Subject | View Object

Appears in Networks:

p(HGNC:HSP90AB1) association bp(GO:"embryo development") View Subject | View Object

Appears in Networks:

p(HGNC:HSP90AB1) association bp(GO:"cell maturation") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Germ Cells

p(HGNC:HSP90AB1) association bp(GO:"cytoskeleton organization") View Subject | View Object

Appears in Networks:

p(HGNC:HSP90AB1) association bp(GO:"signal transduction") View Subject | View Object

Appears in Networks:

p(HGNC:HSP90AB1) association bp(GO:"adaptation of signaling pathway") View Subject | View Object

Appears in Networks:

path(MESH:"Neoplasm Metastasis") association p(HGNC:HSP90AA1) View Subject | View Object

Appears in Networks:

Evidence 66a2cbafb9
JSON

Hsp90 and Hop are both involved in the CMA system;

p(HGNC:STIP1) association bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Appears in Networks:

bp(GO:"chaperone-mediated autophagy") association p(FPLX:HSP90) View Subject | View Object

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bp(GO:"chaperone-mediated autophagy") association p(HGNC:STIP1) View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) association bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Appears in Networks:

Evidence 4dff91539d
JSON

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).

p(FPLX:HSP90) association bp(HBP:Proteostasis) View Subject | View Object

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bp(HBP:Proteostasis) association p(FPLX:HSP90) View Subject | View Object

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Evidence 17b986888a
JSON

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).

bp(MESH:Aging) association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") association bp(MESH:Aging) View Subject | View Object

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Evidence 7560c7f17d
JSON

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.

bp(MESH:Aging) decreases bp(GO:"protein folding") View Subject | View Object

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bp(MESH:Aging) increases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

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bp(MESH:Aging) decreases bp(MESH:Proteolysis) View Subject | View Object

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Evidence 86d9398ac3
JSON

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).

bp(MESH:Aging) decreases act(p(FPLX:Proteasome)) View Subject | View Object

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bp(MESH:Aging) decreases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

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Evidence f0b2a504cc
JSON

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).

bp(MESH:Aging) decreases act(p(FPLX:Proteasome)) View Subject | View Object

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p(FPLX:HSP90) increases act(p(FPLX:Proteasome)) View Subject | View Object

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Evidence c4c2101ffd
JSON

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

bp(MESH:Aging) decreases bp(GO:"chaperone-mediated autophagy") View Subject | View Object

Appears in Networks:

Evidence 5b11833867
JSON

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

bp(MESH:Aging) decreases p(HGNC:PPID) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:PPID) View Subject | View Object

Appears in Networks:

Evidence aed4c9af7a
JSON

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

bp(MESH:Aging) decreases p(HGNC:PPP5C) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

bp(MESH:Aging) decreases p(HGNC:AHSA1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

bp(MESH:Aging) decreases p(HGNC:PPID) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

bp(MESH:Aging) decreases p(HGNC:FKBP4) View Subject | View Object

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Annotations
MeSH
Brain

bp(MESH:Aging) decreases p(HGNC:STIP1) View Subject | View Object

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Annotations
MeSH
Brain

bp(MESH:Aging) decreases p(HGNC:PTGES3) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence c9b370d984
JSON

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).

path(MESH:"Alzheimer Disease") increases p(HGNC:FKBP5) View Subject | View Object

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bp(MESH:Aging) increases p(HGNC:FKBP5) View Subject | View Object

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Evidence 69a6a859d8
JSON

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

bp(MESH:Aging) increases p(HGNC:FKBP5) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 5e7d1497cf
JSON

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

bp(MESH:Aging) decreases p(HGNC:PPP5C) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence e32ce5e1a5
JSON

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.

bp(MESH:Aging) decreases p(HGNC:AHSA1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:AHSA1) increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

Evidence 7fab0d7424
JSON

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).

bp(MESH:Aging) increases p(FPLX:HSP90) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
peripheral blood mononuclear cell

Evidence fef53adf1a
JSON

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

bp(MESH:Aging) decreases p(FPLX:HSP90) View Subject | View Object

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Annotations
MeSH
Brain

Evidence c8aad96166
JSON

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).

bp(MESH:Aging) decreases p(FPLX:HSP90) View Subject | View Object

Appears in Networks:
Annotations
Uberon
prefrontal cortex
Uberon
superior frontal gyrus

Evidence f3418d28a1
JSON

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.

bp(MESH:Aging) increases p(FPLX:HSP90, pmod(Ph)) View Subject | View Object

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bp(MESH:Aging) increases p(FPLX:HSP90, pmod(Ac)) View Subject | View Object

Appears in Networks:

bp(MESH:Aging) increases p(FPLX:HSP90, pmod(NO)) View Subject | View Object

Appears in Networks:

bp(MESH:Aging) increases p(FPLX:HSP90, pmod(Ub)) View Subject | View Object

Appears in Networks:

Evidence 900cf62efa
JSON

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

p(FPLX:HSP90) regulates a(HBP:"Tau aggregates") View Subject | View Object

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p(FPLX:HSP90) regulates path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Appears in Networks:

Evidence 4ffe9c7fb0
JSON

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

act(p(FPLX:HSP90), ma(GO:"ATPase activity")) increases path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:

Evidence 98cf9dee37
JSON

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

p(FPLX:HSP90) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

p(FPLX:HSP90) increases p(HGNC:MAPT, var("?")) View Subject | View Object

Appears in Networks:

Evidence f4083f0f90
JSON

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).

complex(p(FPLX:HSP90), p(HGNC:CDC37)) increases p(HGNC:GSK3B) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

complex(p(FPLX:HSP90), p(HGNC:CDC37)) increases p(HGNC:MAPK13) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

act(p(HGNC:GSK3B), ma(kin)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

act(p(HGNC:MAPK13), ma(kin)) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence dbb0d424e8
JSON

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

p(HGNC:CDC37) increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence f12c669125
JSON

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

p(HGNC:FKBP4) increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

Evidence 727ac12441
JSON

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

p(HGNC:PTGES3) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

Appears in Networks:

Evidence 6d838f080d
JSON

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).

p(HGNC:PTGES3) decreases path(MESH:"Protein Aggregation, Pathological") View Subject | View Object

Appears in Networks:

Evidence 908a8e1608
JSON

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).

p(HGNC:PTGES3) increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

p(HGNC:PTGES3) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence bba1a77b09
JSON

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).

p(HGNC:PTGES3) decreases bp(GO:"cell death in response to oxidative stress") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:misfolding)) increases bp(GO:"cell death in response to oxidative stress") View Subject | View Object

Appears in Networks:

Evidence 01b486fc26
JSON

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

p(HGNC:STIP1) decreases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence 0a46050163
JSON

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).

complex(p(FPLX:HSP90), p(HGNC:FKBP5)) increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

Evidence 31940e657c
JSON

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

complex(p(FPLX:HSP90), p(HGNC:FNIP1)) decreases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

Appears in Networks:

Evidence abb57b3a54
JSON

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

complex(p(FPLX:HSP90), p(HGNC:FNIP1), p(HGNC:FNIP2)) increases p(HGNC:FLCN) View Subject | View Object

Appears in Networks:

Evidence 40c0231ba2
JSON

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).

p(HGNC:PPID) decreases a(HBP:"Tau fibrils") View Subject | View Object

Appears in Networks:

p(HGNC:PPID) decreases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

p(HGNC:PPID) increases bp(GO:memory) View Subject | View Object

Appears in Networks:

p(HGNC:PPID) decreases bp(GO:"neuron apoptotic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence ff67f261d3
JSON

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

act(p(HGNC:PPP5C)) decreases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:MAPT, pmod(Ph)) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence a041bcd90a
JSON

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).

p(HGNC:S100A1) increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

p(HGNC:S100A1) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence bd8a15d9f5
JSON

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

p(FPLX:HSP90, pmod(Ac)) decreases complex(a(CHEBI:ATP), p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

Evidence a231918b5f
JSON

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

p(FPLX:HSP90, pmod(NO)) decreases act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

p(FPLX:HSP90, pmod(Ub)) decreases act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

Evidence f13bf2aeca
JSON

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).

p(FPLX:HSP90, pmod(Ph)) decreases act(p(FPLX:HSP90)) View Subject | View Object

Appears in Networks:

Evidence e9b978f392
JSON

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.

p(HGNC:AHSA1) increases act(p(FPLX:HSP90), ma(GO:"ATPase activity")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence 57bdf635d6
JSON

Aha1 levels have been shown to increase with AD.

p(HGNC:AHSA1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:AHSA1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence f770baeeb8
JSON

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).

p(HGNC:AHSA1) increases a(HBP:"Tau oligomers") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:AHSA1) increases bp(GO:"neuron apoptotic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence 54bc8e54c7
JSON

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

p(HGNC:AHSA1) association path(MESH:"Cystic Fibrosis") View Subject | View Object

Appears in Networks:

path(MESH:"Cystic Fibrosis") association p(HGNC:AHSA1) View Subject | View Object

Appears in Networks:

Evidence a5ebc80d0e
JSON

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).

p(HGNC:STUB1) association path(MESH:"Huntington Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:STUB1) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:STUB1) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:STUB1) association path(MESH:"Cystic Fibrosis") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:STUB1) association path(MESH:Neoplasms) View Subject | View Object

Appears in Networks:
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MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") association p(HGNC:STUB1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Cystic Fibrosis") association p(HGNC:STUB1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Huntington Disease") association p(HGNC:STUB1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Parkinson Disease") association p(HGNC:STUB1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:Neoplasms) association p(HGNC:STUB1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence f104223e46
JSON

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

p(HGNC:STUB1) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:STUB1) increases deg(p(HGNC:MAPT, pmod(HBP:misfolding))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence d789293948
JSON

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

p(HGNC:TOMM34) decreases path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:
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MeSH
Cerebral Cortex

Evidence 3d8684c166
JSON

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).

path(MESH:"Alzheimer Disease") decreases p(HGNC:FKBP4) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence 0d2c90057c
JSON

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

path(MESH:"Alzheimer Disease") decreases act(p(HGNC:PPP5C)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

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.