Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases
Abstract
:1. Introduction
2. Hsp70 and Its Co-Chaperones
2.1. Hsp70 Structure and Chaperone Cycle
2.2. Hsp70 and Its Co-Chaperones in Neurodegenerative Diseases
2.3. Hsp70 Co-Chaperone Interaction Inhibitors
3. Hsp90 and Its Co-Chaperones
3.1. Hsp90 Structure and Chaperone Cycles
3.2. Hsp90 and Its Co-Chaperones in Neurodegenerative Diseases and Their PPI Inhibitors
3.2.1. Hsp90–Cdc37 Interaction
Natural Products
Cdc37 Peptides
Small-Molecule Inhibitors
3.2.2. Hsp90–Aha1 Interaction
3.2.3. Hsp90–p23 Interaction
3.2.4. Hsp90–Hop Interaction
3.2.5. Hsp90 and Other TPR Co-Chaperones Interactions
Hsp90 TPR Co-Chaperones in Neurodegenerative Diseases
Hsp90–TPR Co-Chaperone Interaction Inhibitors
Hsp90/Hsp70 Interaction with Dicarboxylate Clamp TPR (dcTPR) Co-Chaperones
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Co-Chaperone | Full Name | Interacting Domain in Co-chaperone | Binding Site in HSP90 | Function | Disease | Cellular Processes |
---|---|---|---|---|---|---|
CDC37 | Cell division cycle 37 | MD, NTD | NTD, MD | Prevents closure of the “lid” in HSP90;Specific for maturation of kinases | AD, PD, ALS, FTLD | Stabilizes tau via Hsp90 and regulates the stability of distinct tau kinases, specifically Cdk5 and Akt [31]; Preserves TDP-43 [32]; Its client kinases include DYRK1A [33] Stabilizes LRRK2 [34]; Stabilizes PINK1 and influences its subcellular distribution [35,36] |
Aha1 | Activator of Hsp90 ATPase homolog 1 | NTD, CTD | NTD, MD | Stimulates ATPase activity of HSP90 | AD | Increases tau fibril formation, Aha1 overexpression in rTg4510 mouse increases tau accumulation, leading to both neuron loss and cognitive deficits [37]. Aha1 overexpression in aged wild-type mice impairs associative learning and promotes tau phosphorylation [38]. |
p23 (Sba1 in yeast) | Co-chaperone p23 | NTD | NTD, MD | Stabilizes the HSP90 closed 2 state; Inhibits Hsp90 ATPase activity | AD, PD | Knockdown of p23 reduces both total and phosphorylated tau levels [39]. Contributes to neurotoxicity in PD [40]. |
Hop (Sti1) | Hsp70-Hsp90 organizing protein (stress-inducible phosphoprotein 1) | TPR | CTD, MD | Transfers clients from Hsp70 to Hsp90; Inhibits Hsp90 ATPase activity | HD, AD, Prion diseases | Hop overexpression in yeast inhibits the toxicity of HTT103Q and reorganizes small HTT103Q foci into larger assemblies [41]. Hop downregulation enhances tau toxicity in the fly model of tauopathy [42]. Binds to PrPC and promotes calcium influx through α7nAChRs [43]. Inhibits Aβ oligomers’ binding to PrPC and prevents synaptic loss, neuronal death, and depression of long-term potentiation induced by Aβ oligomers [44]. |
PP5 (Ppt1 in yeast) | Protein phosphatase 5 | TPR | CTD | Dephosphorylates Hsp90; Dephosphorylates Cdc37 | AD | Dephosphorylates tau and its activity decreases in AD neocortex [45]. Protects primary neuron death induced by Aβ [46]. |
CHIP | C terminus of Hsp70-interacting protein | TPR | CTD | E3 ubiquitin ligase | AD, PD, HD | Promotes the degradation of phosphorylated tau [39,47]. Reduces α-synuclein oligomerization and mediates α-synuclein degradation [48,49]. Reduces the uptake of α-synuclein fibrils by neuro-2a cells [50]. Promotes the degradation of LRRK2 [51,52]. CHIP overexpression promotes the degradation of polyglutamine-expanded HTT or ataxin-3 [53]. Suppresses polyglutamine aggregation and toxicity [54]. |
FKBP51 | FK506 binding protein 51 kDa | TPR | CTD | Peptidyl-prolyl isomerase activity; Participates in Hsp90-steroid receptor complex; Generally regulates Hsp90 conformational cycle | AD, PD, HD | Enhances the production of tau oligomers and prevents tau degradation [55]. Increases with age in the mouse brain, and its expression is higher in AD patients [55,56]. Involved in Pink1′s regulation of AKT on neuronal survival [57]. FKBP51 downregulation reduces mutant HTT levels in HD models both in vitro and in vivo [58]. |
FKBP52 | FK506 binding protein 52 kDa | TPR | CTD | Peptidyl-prolyl isomerase activity; Participates in Hsp90-steroid receptor complex; Generally regulates Hsp90 conformational cycle | AD, PD | Induces aggregation of multiple tau species in vitro [59,60,61]. FKBP52 overexpression in the hippocampus leads to cognitive impairments and neurotoxicity in aged wild-type mice and rTg4510 transgenic mice [38,62]. FKBP52 levels are abnormally low in the frontal cortex of AD brains [63]. Suppresses Aβ toxicity and increases the lifespan of Drosophila, which expresses Aβ peptides [64]. Accelerates α-synuclein aggregation and neuronal cell death [65]. Generates immune responses to α-synuclein-based immunizations in mice [66]. |
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Wang, L.; Bergkvist, L.; Kumar, R.; Winblad, B.; Pavlov, P.F. Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases. Cells 2021, 10, 2596. https://doi.org/10.3390/cells10102596
Wang L, Bergkvist L, Kumar R, Winblad B, Pavlov PF. Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases. Cells. 2021; 10(10):2596. https://doi.org/10.3390/cells10102596
Chicago/Turabian StyleWang, Lisha, Liza Bergkvist, Rajnish Kumar, Bengt Winblad, and Pavel F. Pavlov. 2021. "Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases" Cells 10, no. 10: 2596. https://doi.org/10.3390/cells10102596
APA StyleWang, L., Bergkvist, L., Kumar, R., Winblad, B., & Pavlov, P. F. (2021). Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases. Cells, 10(10), 2596. https://doi.org/10.3390/cells10102596