Roles of molecular chaperones in protein misfolding diseases

2004 ◽  
Vol 15 (1) ◽  
pp. 17-29 ◽  
Author(s):  
José M Barral ◽  
Sarah A Broadley ◽  
Gregor Schaffar ◽  
F.Ulrich Hartl
Keyword(s):  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Misfolding Diseases

scholarly journals Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly

2020 ◽  
Vol 21 (23) ◽  
pp. 9186
Author(s):  
Rubén Hervás ◽  
Javier Oroz
Keyword(s):  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Cell Damage ◽  
Protective Role ◽  
Soluble Proteins ◽  
Protein Deposits ◽  
Client Proteins ◽  
Recognition Motifs ◽  
Misfolding Diseases

Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.

scholarly journals Exploring Charged Polymeric Cyclodextrins for Biomedical Applications

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1724
Author(s):  
Noemi Bognanni ◽  
Francesco Bellia ◽  
Maurizio Viale ◽  
Nadia Bertola ◽  
Graziella Vecchio
Keyword(s):  
Molecular Chaperones ◽  
Potential Application ◽  
Protein Misfolding ◽  
Biomedical Applications ◽  
Drug Carriers ◽  
Doxorubicin Toxicity ◽  
A2780 Cell ◽  
A2780 Cell Line ◽  
Cyclodextrin Polymers ◽  
Misfolding Diseases

Over the years, cyclodextrin uses have been widely reviewed and their proprieties provide a very attractive approach in different biomedical applications. Cyclodextrins, due to their characteristics, are used to transport drugs and have also been studied as molecular chaperones with potential application in protein misfolding diseases. In this study, we designed cyclodextrin polymers containing different contents of β- or γ-cyclodextrin, and a different number of guanidinium positive charges. This allowed exploration of the influence of the charge in delivering a drug and the effect in the protein anti-aggregant ability. The polymers inhibit Amiloid β peptide aggregation; such an ability is modulated by both the type of CyD cavity and the number of charges. We also explored the effect of the new polymers as drug carriers. We tested the Doxorubicin toxicity in different cell lines, A2780, A549, MDA-MB-231 in the presence of the polymers. Data show that the polymers based on γ-cyclodextrin modified the cytotoxicity of doxorubicin in the A2780 cell line.

scholarly journals Infrared nanospectroscopy reveals the molecular interaction fingerprint of an aggregation inhibitor with single Aβ42 oligomers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Francesco Simone Ruggeri ◽  
Johnny Habchi ◽  
Sean Chia ◽  
Robert I. Horne ◽  
Michele Vendruscolo ◽  
...  
Keyword(s):  
Small Molecules ◽  
Single Molecule ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Chemical Sensitivity ◽  
Incomplete Knowledge ◽  
Parkinson’S Diseases ◽  
Aggregation Inhibitor ◽  
Misfolding Diseases

AbstractSignificant efforts have been devoted in the last twenty years to developing compounds that can interfere with the aggregation pathways of proteins related to misfolding disorders, including Alzheimer’s and Parkinson’s diseases. However, no disease-modifying drug has become available for clinical use to date for these conditions. One of the main reasons for this failure is the incomplete knowledge of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and interfere with their aggregation pathways. Here, we leverage the single molecule morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the structure and interaction between single Aβ42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, which is able to prevent Aβ42 aggregation in vitro and reverses its neurotoxicity in cell and animal models of Alzheimer’s disease. Our results demonstrate that the carboxyl group of this compound interacts with Aβ42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as a powerful tool in structure-based drug discovery for protein misfolding diseases.

scholarly journals SAR by kinetics for drug discovery in protein misfolding diseases

2018 ◽  
Vol 115 (41) ◽  
pp. 10245-10250 ◽  
Author(s):  
Sean Chia ◽  
Johnny Habchi ◽  
Thomas C. T. Michaels ◽  
Samuel I. A. Cohen ◽  
Sara Linse ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Misfolding ◽  
Amyloid Beta Peptide ◽  
Oligomer Formation ◽  
Chemical Derivatives ◽  
Structure Activity ◽  
Beta Peptide ◽  
Misfolding Diseases ◽  
Aβ Oligomer

To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure−activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aβ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.

scholarly journals Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity

2020 ◽  
Author(s):  
Lilian Tsai-Wei Lin ◽  
Abdul Razzaq ◽  
Sonja E. Di Gregorio ◽  
Soojie Hong ◽  
Brendan Charles ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Central Feature ◽  
Dependent Manner ◽  
Cellular Toxicity ◽  
Inclusion Formation ◽  
Dose Dependent ◽  
Lateral Sclerosis ◽  
Strong Capacity

AbstractProtein misfolding is a central feature of most neurodegenerative diseases. Molecular chaperones can modulate the toxicity associated with protein misfolding, but it remains elusive which molecular chaperones and co-chaperones interact with specific misfolded proteins. TDP-43 misfolding and inclusion formation is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Using yeast and mammalian neuronal cells we find that Hsp90 and its co-chaperones have a strong capacity to alter TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity. Our data also demonstrate that impaired Hsp90 function sensitizes cells to TDP-43 toxicity. We further show that the co-chaperone Sti1 specifically interacts with and modulates TDP-43 toxicity in a dose-dependent manner. Our study thus uncovers a previously unrecognized tie between Hsp90, Sti1, TDP-43 misfolding, and its cellular toxicity.

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

2018 ◽  
Vol 19 (9) ◽  
pp. 2603 ◽  
Author(s):  
Claudia Campanella ◽  
Andrea Pace ◽  
Celeste Caruso Bavisotto ◽  
Paola Marzullo ◽  
Antonella Marino Gammazza ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Point Of View ◽  
Toxic Species ◽  
Shock Proteins

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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