17-AAG improves cognitive process and increases heat shock protein response in a model lesion with Aβ25–35

Ortega, Laura; Calvillo, Minerva; Luna, Félix; Pérez-Severiano, Francisca; Rubio-Osornio, Moisés; Guevara, Jorge; Limón, Ilhuicamina Daniel

doi:10.1016/j.npep.2014.04.006

Cited by 24 publications

(16 citation statements)

References 60 publications

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“…Several studies showed that treatment with 17AAG upregulates HSP70 [38, 39] that participates in intracellular signaling pathways by binding different co-chaperones such as CHIP [40]. HSP70 functions as ATP-dependent molecular chaperone through activation of the ERK signaling [41].…”

Section: Resultsmentioning

confidence: 99%

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AQP2 Abundance is Regulated by the E3-Ligase CHIP Via HSP70

Centrone

Ranieri

Mise

et al. 2017

Cell Physiol Biochem

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Background/Aims: AQP2 expression is mainly controlled by vasopressin-dependent changes in protein abundance which is in turn regulated by AQP2 ubiquitylation and degradation, however the proteins involved in these processes are largely unknown. Here, we investigated the potential role of the CHIP E3 ligase in AQP2 regulation. Methods: MCD4 cells and kidney slices were used to study the involvement of the E3 ligase CHIP on AQP2 protein abundance by cell homogenization and immunoprecipitation followed by immunoblotting. Results: We found that AQP2 complexes with CHIP in renal tissue. Expression of CHIP increased proteasomal degradation of AQP2 and HSP70 abundance, a molecular signature of HSP90 inhibition. Increased HSP70 level, secondary to CHIP expression, promoted ERK signaling resulting in increased AQP2 phosphorylation at S261. Phosphorylation of AQP2 at S256 and T269 were instead downregulated. Next, we investigated HSP70 interaction with AQP2, which is important for endocytosis. Compared with AQP2-wt, HSP70 binding decreased in AQP2-S256D and AQP2-S256D-S261D, while increased in AQP2-S256D-S261A. Surprisingly, expression of CHIP-delUbox, displaying a loss of E3 ligase activity, still induced AQP2 degradation, indicating that CHIP does not ubiquitylate and degrade AQP2 itself. Conversely, the AQP2 half-life was increased upon the expression of CHIP-delTPR a domain which binds Hsc70/HSP70 and HSP90. HSP70 has been reported to bind other E3 ligases such as MDM2. Notably, we found that co-expression of CHIP and MDM2 increased AQP2 degradation, whereas co-expression of CHIP with MDM2-delRING, an inactive form of MDM2, impaired AQP2 degradation. Conclusion: Our findings indicate CHIP as a master regulator of AQP2 degradation via HSP70 that has dual functions: (1) as chaperone for AQP2 and (2) as an anchoring protein for MDM2 E3 ligase, which is likely to be involved in AQP2 degradation.

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Section: Resultsmentioning

confidence: 99%

“…5). Chemical inhibition of HSP90, with 17AAG, also increased HSP70 expression [39, 55], that can sequester the clients released by the inactive HSP90 and trigger their degradation. Inhibition of HSP90 with 17AAG reduces AQP2 expression level in MCD4 cell not transfected with CHIP (mock).…”

Section: Discussionmentioning

confidence: 99%

AQP2 Abundance is Regulated by the E3-Ligase CHIP Via HSP70

Centrone

Ranieri

Mise

et al. 2017

Cell Physiol Biochem

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“…administration of 17-AAG improved cognitive process and upregulated Hsp70 and Hsp27 expression. A possible therapeutic approach to the use of GA should lead to discovery and use of its less toxic derivatives, such as 17-AAG (Ortega et al 2014). Although the mechanism through which Aβ toxicity generates progressive cognitive and memory decline is explored extensively, the precise molecular pathway to explain the whole Aβ toxicity manifestations remains an open question.…”

Section: Discussionmentioning

confidence: 99%

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

Zare

Motamedi

Digaleh

et al. 2015

Cell Stress and Chaperones

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One of the neuropathological hallmarks of Alzheimer's disease (AD) is the accumulation of betaamyloid peptides (Aβ) in senile plaques. Aβ-induced oxidative stress is believed to be responsible for degeneration and apoptosis of neurons and consequent cognitive and memory deficits. Here, we investigated the possible neuroprotective effect of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) against amyloid pathogenesis in adult male Wistar rats. GA or vehicle was injected into the lateral cerebral ventricles of rats 24 h before injection of Aβ (1-42) in CA1 area of hippocampus. The learning and memory of the rats were assessed 7 days after injection of Aβ using passive avoidance (PA) task. As potential contributing factors in Aβ-induced memory decline, we evaluated apoptotic markers and also used terminal-transferase UTP nick end labeling (TUNEL) technique to detect apoptosis in the hippocampus of Aβ-injected rats. Our behavioral data suggest that GA pretreatment can significantly suppress memory deficits in Aβ-injected rats. There was also not only a marked increase in Hsp70 level but also upregulated 70 kDa ribosomal protein S6 kinase (p70S6K) in the hippocampus of GA-treated groups with a reduction in apoptotic factors including caspase-3, poly (ADP-ribose) polymerase, Bax/Bcl-2 ratio, and TUNELpositive cells as well. Thus, we conclude that GA exerts its protective effects against Aβ (1-42) toxicity and memory deficits, at least in part, by upregulating of Hsp70 and P70S6K.

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“…Since, Hsp90 activities are ATP-dependent, this complex can be targeted by small molecules that compete with ATP for binding to Hsp90. Radicicol, NVP-HSP990, geldanamycin and geldanamycin-derived 17-allylaminogeldanamycin are Hsp90 inhibitors that act in this way and have been investigated for the treatment of NDs [ 72 , 75 , 168 , 169 ]. In HD mouse models, NVP-HSP990-induced induction of the HSR in CNS tissues but this effect declined with increasing age of mice and despite a 20% decline in inclusion load, no extension of life was observed [ 75 ].…”

Section: Studying the Therapeutic Effects Of Increasing Hsr Componentmentioning

confidence: 99%

The heat shock response in neurons and astroglia and its role in neurodegenerative diseases

Gil

Ooi

Yerbury

et al. 2017

Mol Neurodegeneration

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Protein inclusions are a predominant molecular pathology found in numerous neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington’s disease. Protein inclusions form in discrete areas of the brain characteristic to the type of neurodegenerative disease, and coincide with the death of neurons in that region (e.g. spinal cord motor neurons in amyotrophic lateral sclerosis). This suggests that the process of protein misfolding leading to inclusion formation is neurotoxic, and that cell-autonomous and non-cell autonomous mechanisms that maintain protein homeostasis (proteostasis) can, at times, be insufficient to prevent protein inclusion formation in the central nervous system. The heat shock response is a pro-survival pathway induced under conditions of cellular stress that acts to maintain proteostasis through the up-regulation of heat shock proteins, a superfamily of molecular chaperones, other co-chaperones and mitotic regulators. The kinetics and magnitude of the heat shock response varies in a stress- and cell-type dependent manner. It remains to be determined if and/or how the heat shock response is activated in the different cell-types that comprise the central nervous system (e.g. neurons and astroglia) in response to protein misfolding events that precede cellular dysfunctions in neurodegenerative diseases. This is particularly relevant considering emerging evidence demonstrating the non-cell autonomous nature of amyotrophic lateral sclerosis and Huntington’s disease (and other neurodegenerative diseases) and the destructive role of astroglia in disease progression. This review highlights the complexity of heat shock response activation and addresses whether neurons and glia sense and respond to protein misfolding and aggregation associated with neurodegenerative diseases, in particular Huntington’s disease and amyotrophic lateral sclerosis, by inducing a pro-survival heat shock response.

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17-AAG improves cognitive process and increases heat shock protein response in a model lesion with Aβ25–35

Cited by 24 publications

References 60 publications

AQP2 Abundance is Regulated by the E3-Ligase CHIP Via HSP70

AQP2 Abundance is Regulated by the E3-Ligase CHIP Via HSP70

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

The heat shock response in neurons and astroglia and its role in neurodegenerative diseases

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