Protein‐misfolding diseases and chaperone‐based therapeutic approaches

Abstract

A large number of neurodegenerative diseases in humans result from protein misfolding and aggregation. Protein misfolding is believed to be the primary cause of Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeldt–Jakob disease, cystic fibrosis, Gaucher's disease and many other degenerative and neurodegenerative disorders. Cellular molecular chaperones, which are ubiquitous, stress‐induced proteins, and newly found chemical and pharmacological chaperones have been found to be effective in preventing misfolding of different disease‐causing proteins, essentially reducing the severity of several neurodegenerative disorders and many other protein‐misfolding diseases. In this review, we discuss the probable mechanisms of several protein‐misfolding diseases in humans, as well as therapeutic approaches for countering them. The role of molecular, chemical and pharmacological chaperones in suppressing the effect of protein misfolding‐induced consequences in humans is explained in detail. Functional aspects of the different types of chaperones suggest their uses as potential therapeutic agents against different types of degenerative diseases, including neurodegenerative disorders.

Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria

“…Missense substitutions result in proteins that are unable to fold efficiently into their native conformation, that is, the most energetically favorable state. This may lead to either accumulation of toxic aggregates or increased degradation and loss of metabolic or cellular functions (17,18).…”

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

“…In fact, most pharmacological chaperones identified to date are competitive inhibitors/antagonists of the protein in question. Logically, since an appropriately formed active site generally requires a properly folded protein, inhibitors/antagonists at these active sites are likely, in the ER, to preferentially stabilize native proteins and native-like intermediates [20,21]. This potential for competitive antagonists/inhibitors to act as chaperones creates a role for high-throughput analysis to rapidly screen large libraries of compounds for inhibitors that could be potential pharmacological chaperones.…”

“…Much like molecular chaperones they promote the folding of a range of proteins. A subset of the chemical chaperones is that of the pharmacological chaperones, which act with specificity for a particular protein and are frequently protein antagonists [15,[20][21][22].…”

“…One such strategy involves the use of chemical chaperones to augment the native action of molecular chaperones or recover specific misfolded proteins, prevent aggregation, and hence restore overall cell health. Indeed, studies have reported promising results regarding the use of chemical chaperones to treat disorders caused by protein misfolding [19][20][21]. In this review, we examine the evidence of ER stress, the role of chaperones, and the pharmacological potential of chaperone compounds for study in AMD.…”

Chaperons pharmacologiques

“…< agir de concert pour provoquer un état pathologique (la rétinite pigmentaire par exemple, voir plus loin). Le repliement défectueux de protéines qui caractérise les maladies dites « conformationnelles » [5,6] dont il sera question dans cette revue résulte de la présence de mutations dans les gènes correspondants de ces proté ines. Ces mutations sont transmissibles de géné-ration en génération ou acquises spontanément.…”