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

Campanella, Claudia; Pace, Andrea; Bavisotto, Celeste Caruso; Marzullo, Paola; Gammazza, Antonella Marino; Buscemi, Silvestre; Piccionello, Antonio Palumbo

doi:10.3390/ijms19092603

Cited by 118 publications

(79 citation statements)

References 139 publications

(203 reference statements)

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“…However, this chaperonin plays various other roles in health and disease, particularly as a pathogenic factor in a range of inherited and acquired chaperonopathies (Macario and Conway de Macario, 2005;Cappello et al, 2008Cappello et al, , 2013Cappello et al, , 2014Marino Gammazza et al, 2017b;Hoter et al, 2019;van Eden et al, 2019). For these reasons, interest in Hsp60 has been steadily increasing in recent years, especially because it holds promise for developing new diagnostic and therapeutic procedures pertinent to common and serious chaperonopathies such as various types of cancer, and inflammatory and autoimmune disorders as well as for a range of neurodegenerative diseases (Macario and Conway de Macario, 2005;Cappello et al, 2008;Bross et al, 2012;Cappello et al, 2013Cappello et al, , 2014Marino Gammazza et al, 2016Campanella et al, 2018;Meng et al, 2018;Hoter et al, 2019;van Eden et al, 2019). For example, Hsp60 inhibitors and modulators are being actively evaluated as novel anti-cancer agents (Wang et al, 2013;Cappello et al, 2014;Meng et al, 2018;Stevens et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Hsp60 Post-translational Modifications: Functional and Pathological Consequences

Bavisotto

Alberti

Vitale

et al. 2020

Front. Mol. Biosci.

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Hsp60 is a chaperone belonging to the Chaperonins of Group I and typically functions inside mitochondria in which, together with the co-chaperonin Hsp10, maintains protein homeostasis. In addition to this canonical role, Hsp60 plays many others beyond the mitochondria, for instance in the cytosol, plasma-cell membrane, extracellular space, and body fluids. These non-canonical functions include participation in inflammation, autoimmunity, carcinogenesis, cell replication, and other cellular events in health and disease. Thus, Hsp60 is a multifaceted molecule with a wide range of cellular and tissue locations and functions, which is noteworthy because there is only one hsp60 gene. The question is by what mechanism this protein can become multifaceted. Likely, one factor contributing to this diversity is post-translational modification (PTM). The amino acid sequence of Hsp60 contains many potential phosphorylation sites, and other PTMs are possible such as O-GlcNAcylation, nitration, acetylation, S-nitrosylation, citrullination, oxidation, and ubiquitination. The effect of some of these PTMs on Hsp60 functions have been examined, for instance phosphorylation has been implicated in sperm capacitation, docking of H2B and microtubule-associated proteins, mitochondrial dysfunction, tumor invasiveness, and delay or facilitation of apoptosis. Nitration was found to affect the stability of the mitochondrial permeability transition pore, to inhibit folding ability, and to perturb insulin secretion. Hyperacetylation was associated with mitochondrial failure; S-nitrosylation has an impact on mitochondrial stability and endothelial integrity; citrullination can be pro-apoptotic; oxidation has a role in the response to cellular injury and in cell migration; and ubiquitination regulates interaction with the ubiquitin-proteasome system. Future research ought to determine which PTM causes which variations in the Hsp60 molecular properties and functions, and which of them are pathogenic, causing chaperonopathies. This is an important topic considering the number of acquired Hsp60 chaperonopathies already cataloged, many of which are serious diseases without efficacious treatment.

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Section: Introductionmentioning

confidence: 99%

Hsp60 Post-translational Modifications: Functional and Pathological Consequences

Bavisotto

Alberti

Vitale

et al. 2020

Front. Mol. Biosci.

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“…Indeed, curcumin's effects can also be related to the direct interaction with this chaperone, suggesting a positive effect on the HSP60/HSP10 complex or for client protein ligation. While the possible mode of action of HSP60 inhibitors is well established [61][62][63], the binding site of curcumin for HSP60/HSP10 folding machine is unknown, and, to the best of our knowledge, this is the first case of enhancer of this CS.…”

Section: Discussionmentioning

confidence: 90%

Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells

Bavisotto

Gammazza

Cascio

et al. 2020

IJMS

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The fundamental challenge in fighting cancer is the development of protective agents able to interfere with the classical pathways of malignant transformation, such as extracellular matrix remodeling, epithelial–mesenchymal transition and, alteration of protein homeostasis. In the tumors of the brain, proteotoxic stress represents one of the main triggering agents for cell transformation. Curcumin is a natural compound with anti-inflammatory and anti-cancer properties with promising potential for the development of therapeutic drugs for the treatment of cancer as well as neurodegenerative diseases. Among the mediators of cancer development, HSP60 is a key factor for the maintenance of protein homeostasis and cell survival. High HSP60 levels were correlated, in particular, with cancer development and progression, and for this reason, we investigated the ability of curcumin to affect HSP60 expression, localization, and post-translational modifications using a neuroblastoma cell line. We have also looked at the ability of curcumin to interfere with the HSP60/HSP10 folding machinery. The cells were treated with 6, 12.5, and 25 µM of curcumin for 24 h, and the flow cytometry analysis showed that the compound induced apoptosis in a dose-dependent manner with a higher percentage of apoptotic cells at 25 µM. This dose of curcumin-induced a decrease in HSP60 protein levels and an upregulation of HSP60 mRNA expression. Moreover, 25 µM of curcumin reduced HSP60 ubiquitination and nitration, and the chaperonin levels were higher in the culture media compared with the untreated cells. Furthermore, curcumin at the same dose was able to favor HSP60 folding activity. The reduction of HSP60 levels, together with the increase in its folding activity and the secretion in the media led to the supposition that curcumin might interfere with cancer progression with a protective mechanism involving the chaperonin.

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“…Insufficient levels of TGFBRs (TGF-beta receptors) are major risk factors of AD, and increasing TGF-beta receptor type-2 (TGFBR2) levels is a potential therapeutic strategy for AD 31 . HSP90 (heat shock protein 90), a chaperone protein, regulated tau pathology by forming macromolecular complexes with co-chaperones and inhibiting HSP90 mitigated tau pathology by proteasomal degradation 32 . Table 1).…”

Section: Discovery Of Disease-associated Microglia Specific Molecularmentioning

confidence: 99%

Multimodal single-cell/nucleus RNA-sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer’s disease

Zhang

Huang

et al. 2020

Preprint

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Systematic identification of molecular networks in disease relevant immune cells of the nervous system is critical for elucidating the underlying pathophysiology of Alzheimer's disease (AD). Two key immune cell types, disease-associated microglia (DAM) and disease-associated astrocytes (DAA), are biologically involved in AD pathobiology. Therefore, uncovering molecular determinants of DAM and DAA will enhance our understanding of AD biology, potentially identifying novel therapeutic targets for AD treatment. Here, we present an integrative, network-based methodology to uncover conserved molecular networks between DAM and DAA. Specifically, we leverage single-cell and single-nucleus RNA sequencing data from both AD transgenic mouse models and AD patient brains, drug-target networks, metabolite-enzyme associations, and the human protein-protein interactome, along with large-scale patient data validation from the MarketScan Medicare Supplemental Database. We find that common and unique molecular network regulators between DAM (i.e, PAK1, MAPK14, and SYK) and DAA (i.e., NFKB1, FOS, and JUN) are significantly enriched by multiple neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1) from genome-wide association studies. Further network analysis reveal shared immune pathways between DAM and DAA, including Fc gamma R-mediated phagocytosis, Th17 cell differentiation, and chemokine signaling. Furthermore, integrative metabolite-enzyme network analyses imply that fatty acids (i.e., elaidic acid) and amino acids (i.e., glutamate, serine, and phenylalanine) may trigger molecular alterations between DAM and DAA. Finally, we prioritize repurposed drug candidates for potential treatment of AD by agents that specifically reverse dysregulated gene expression of DAM or DAA, including an antithrombotic anticoagulant triflusal, a beta2-adrenergic receptor agonist salbutamol, and the steroid medications (fluticasone and mometasone). Individuals taking fluticasone (an approved anti-inflammatory and inhaled corticosteroid) displayed a significantly decreased incidence of AD (hazard ratio (HR) = 0.858, 95% confidence interval [CI] 0.829-0.888, P < 0.0001) in retrospective case-control validation. Furthermore, propensity score matching cohort studies also confirmed an association of mometasone with reduced incidence of AD in comparison to fluticasone (HR =0.921, 95% CI 0.862-0.984, P < 0.0001).

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

Cited by 118 publications

References 139 publications

Hsp60 Post-translational Modifications: Functional and Pathological Consequences

Hsp60 Post-translational Modifications: Functional and Pathological Consequences

Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells

Multimodal single-cell/nucleus RNA-sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer’s disease

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