Alzheimer's Disease and Molecular Chaperones: Current Knowledge and the Future of Chaperonotherapy

Gammazza, Antonella Marino; Bavisotto, Celeste Caruso; Barone, Rosario; Macario, Everly Conway de; Macario, Alberto J. L.

doi:10.2174/1381612822666160518141437

Cited by 39 publications

(25 citation statements)

References 117 publications

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“…There are many data that demonstrated that HSPs regulate protein misfolding in a variety of neurodegenerative diseases, such as AD, probably displaying protective roles and/or acting as pathogenic factors. Indeed, stress-induced proteins like chaperones have been claimed to act as protective molecules for cells of the nervous system [ 20 ]. Many evidences demonstrated that oxidative stress is a feature of AD and PD [ 37 ].…”

Section: Molecular Chaperones and Neurodegenerative Diseasesmentioning

confidence: 99%

“…Under these stress conditions, the expression of the genes encoding HSPs was induced [ 38 ]. Moreover, mitochondrial dysfunction and elevated levels of ROS might create a vicious circle contributing to AD instauration and progression (see Figure 1 ) [ 20 ].…”

Section: Molecular Chaperones and Neurodegenerative Diseasesmentioning

confidence: 99%

“…[ 12 ]. Among molecular chaperones, Heat Shock Proteins (HSPs) are major constituent of the chaperome and Hsp60 [ 13 ], Hsp70 [ 14 , 15 , 16 ] and Hsp90 [ 17 , 18 ] are considered target [ 19 ] of particular relevance in AD [ 20 ] and for many other diseases, including cancer [ 21 , 22 , 23 , 24 ]. In this review, recent advances regarding the role of these three proteins in AD is highlighted from a biological point of view.…”

Section: Introductionmentioning

confidence: 99%

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

Campanella

Pace

Bavisotto

et al. 2018

IJMS

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118

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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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Section: Molecular Chaperones and Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Molecular Chaperones and Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Campanella

Pace

Bavisotto

et al. 2018

IJMS

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118

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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: 89%

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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“…Hsp60 is preeminently a protein-folding machine but it can also stimulate anti-apoptotic mechanisms involving sequestration of Bax-containing complexes thus favoring tumor cell survival [51,55]. However, it has been demonstrated that Hsp60 modified with Olinked N-acetylglucosamine (O-GlcNAcylation) in pancreatic bcells, under hyperglycemic conditions, shows a decreased interaction with Bax leading to cell death [56].…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of replicative senescence

et al. 2017

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a b s t r a c tThe chaperone Hsp60 is pro-carcinogenic in certain tumor types by interfering with apoptosis and with tumor cell death. In these tumors, it is not yet known whether doxorubicin anti-tumor effects include a blockage of the pro-carcinogenic action of Hsp60. We found a doxorubicin dose-dependent viability reduction in a human lung mucoepidermoid cell line that was paralleled by the appearance of cell senescence markers. Concomitantly, intracellular Hsp60 levels decreased while its acetylation levels increased. The data suggest that Hsp60 acetylation interferes with the formation of the Hsp60/p53 complex and/or promote its dissociation, both causing an increase in the levels of free p53, which can then activate the p53-dependent pathway toward cell senescence. On the other hand, acetylated Hsp60 is ubiquitinated and degraded and, thus, the anti-apoptotic effect of the chaperonin is abolished with subsequent tumor cell death. Our findings could help in the elucidation of the molecular mechanisms by which doxorubicin counteracts carcinogenesis and, consequently, it would open new roads for the development of cancer treatment protocols targeting Hsp60.

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Alzheimer's Disease and Molecular Chaperones: Current Knowledge and the Future of Chaperonotherapy

Cited by 39 publications

References 117 publications

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

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

Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells

Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of replicative senescence

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