Translational Shift of HSP90 as a Novel Therapeutic Target from Cancer to Neurodegenerative Disorders: An Emerging Trend in the Cure of Alzheimer's and Parkinson's Diseases

Alam, Qamre; Alam, Mohammad Zubair; Sait, Khalid; Anfinan, Nisreen; Noorwali, Abdul Wahab; Kamal, Mohammad Amjad; Khan, Mohd Sajjad Ahmad; Haque, Absarul

doi:10.2174/1389200218666170728115606

Cited by 26 publications

(25 citation statements)

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“…HSP90B1 gene expression was reduced in the hippocampus of a murine model of type 2 diabetes [37]. This protein also increases the protective heat shock response by suppressing inflammatory signalling pathways in several diseases [38], and it was previously shown that HSP90B1 can increase the IL6 secretion in treated N9 microglial cell line [39], which is in accordance with our findings.…”

Section: Discussionsupporting

confidence: 91%

Relationship between the Plasma Proteome and Changes in Inflammatory Markers after Bariatric Surgery

Fachim

Iqbal

Gibson

et al. 2021

Cells

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Severe obesity is a disease associated with multiple adverse effects on health. Metabolic bariatric surgery (MBS) can have significant effects on multiple body systems and was shown to improve inflammatory markers in previous short-term follow-up studies. We evaluated associations between changes in inflammatory markers (CRP, IL6 and TNFα) and circulating proteins after MBS. Methods: Sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics was performed on plasma samples taken at baseline (pre-surgery) and 6 and 12 months after MBS, and concurrent analyses of inflammatory/metabolic parameters were carried out. The change in absolute abundances of those proteins, showing significant change at both 6 and 12 months, was tested for correlation with the absolute and percentage (%) change in inflammatory markers. Results: We found the following results: at 6 months, there was a correlation between %change in IL-6 and fold change in HSPA4 (rho = −0.659; p = 0.038) and in SERPINF1 (rho = 0.714, p = 0.020); at 12 months, there was a positive correlation between %change in IL-6 and fold change in the following proteins—LGALS3BP (rho = 0.700, p = 0.036), HSP90B1 (rho = 0.667; p = 0.05) and ACE (rho = 0.667, p = 0.05). We found significant inverse correlations at 12 months between %change in TNFα and the following proteins: EPHX2 and ACE (for both rho = −0.783, p = 0.013). We also found significant inverse correlations between %change in CRP at 12 months and SHBG (rho = −0.759, p = 0.029), L1CAM (rho = −0.904, p = 0.002) and AMBP (rho = −0.684, p = 0.042). Conclusion: Using SWATH-MS, we identified several proteins that are involved in the inflammatory response whose levels change in patients who achieve remission of T2DM after bariatric surgery in tandem with changes in IL6, TNFα and/or CRP. Future studies are needed to clarify the underlying mechanisms in how MBS decreases low-grade inflammation.

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Section: Discussionsupporting

confidence: 91%

Relationship between the Plasma Proteome and Changes in Inflammatory Markers after Bariatric Surgery

Fachim

Iqbal

Gibson

et al. 2021

Cells

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“…Together with our studies, these findings lead us to speculate that the stress of a temperature change, either low or high temperature, may increase the level of Hsp90 ( 37 ) and lead to increased γ-secretase complex formation and Aβ production. Hsp90 accounts for 1–2% of protein in a normal, unstressed cell; however, when cells become stressed, the level of Hsp90 increases up to 3–5% ( 38 , 39 , 40 ). Hsp90 is also a key player in protein processing and homeostasis by colocalizing with aggregated proteins in neurodegenerative diseases, particularly in AD and Parkinson's disease ( 41 , 42 ).…”

Section: Discussionmentioning

confidence: 99%

High temperature promotes amyloid β-protein production and γ-secretase complex formation via Hsp90

Noorani

Yamashita

Gao

et al. 2020

Journal of Biological Chemistry

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Alzheimer’s disease (AD) is characterized by neuronal loss and accumulation of amyloid β-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25-40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37°C to 39°C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39°C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF), and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx defective-1 (APH-1) and nicastrin (NCT), but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30°C) compared with those housed at standard room temperature (23°C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.

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“…For example, Hsp90 inhibition might be useful in AD treatment counteracting Tau protein hyperphosphorylation and aggregation. However, also in this case, the research of Hsp90 inhibitors in AD could benefit from previous findings regarding anti-cancer drugs [ 122 ], with many compounds already tested in clinical trials [ 123 ]. The identification of potential Hsp90 inhibitors could be efficiently performed by means of different screening methods including microarray- [ 124 ], virtual- [ 125 , 126 ] or cell-based screening [ 127 ].…”

Section: Hsp90mentioning

confidence: 99%

Heat Shock Proteins in Alzheimer’s Disease: Role and Targeting

Campanella

Pace

Bavisotto

et al. 2018

IJMS

120

104

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Among diseases whose cure is still far from being discovered, Alzheimer’s disease (AD) has been recognized as a crucial medical and social problem. A major issue in AD research is represented by the complexity of involved biochemical pathways, including the nature of protein misfolding, which results in the production of toxic species. Considering the involvement of (mis)folding processes in AD aetiology, targeting molecular chaperones represents a promising therapeutic perspective. This review analyses the connection between AD and molecular chaperones, with particular attention toward the most important heat shock proteins (HSPs) as representative components of the human chaperome: Hsp60, Hsp70 and Hsp90. The role of these proteins in AD is highlighted from a biological point of view. Pharmacological targeting of such HSPs with inhibitors or regulators is also discussed.

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Translational Shift of HSP90 as a Novel Therapeutic Target from Cancer to Neurodegenerative Disorders: An Emerging Trend in the Cure of Alzheimer's and Parkinson's Diseases

Cited by 26 publications

References 0 publications

Relationship between the Plasma Proteome and Changes in Inflammatory Markers after Bariatric Surgery

Relationship between the Plasma Proteome and Changes in Inflammatory Markers after Bariatric Surgery

High temperature promotes amyloid β-protein production and γ-secretase complex formation via Hsp90

Heat Shock Proteins in Alzheimer’s Disease: Role and Targeting

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