Abstract
Protein misfolding and aggregation cause a large number of neurodegenerative diseases in humans due to (i) gain of function as observed in Alzheimer's disease, Huntington's disease, Parkinson's disease, and Prion's disease or (ii) loss of function as observed in cystic fibrosis and alpha1-antitrypsin deficiency. These misfolded proteins could either lead to the formation of harmful amyloids that become toxic for the cells or to be recognized and prematurely degraded by the protein quality control system. An increasing number of studies has indicated that some low-molecular-weight compounds named as chemical chaperones can reverse the mislocalization and/or aggregation of proteins associated with human conformational diseases. These small molecules are thought to non-selectively stabilize proteins and facilitate their folding. In this review, we summarize the probable mechanisms of protein conformational diseases in humans and the use of chemical chaperones and inhibitors as potential therapeutic agents against these diseases. Furthermore, recent advanced experimental and theoretical approaches underlying the detailed mechanisms of protein conformational changes and current structure-based drug designs towards protein conformational diseases are also discussed. It is believed that a better understanding of the mechanisms of conformational changes as well as the biological functions of these proteins will lead to the development and design of potential interfering compounds against amyloid formation associated with protein conformational diseases.
Highlights
Protein misfolding is believed to be the primary cause of several neurodegenerative diseases in humans, such as Alzheimer’s disease (AD), Creutzfeldt-Jakob disease, Gaucher’s disease, Huntington’s disease, Parkinson’s disease, Prion’s disease, cystic fibrosis (CF), α1-antitrypsin deficiency, and many others
The misfolded protein may lead to harmful effects, which can be divided into two categories: (i) gain of function as observed in AD, Huntington’s disease, Parkinson’s disease, and Prion’s disease and (ii) loss of function as in the cases of CF and α1-antitrypsin deficiency.[1]
Proteins that are not able to reach their native states are recognized as misfolded and subsequently targeted to a degradation pathway (Fig. 1C). This is referred to the “protein quality control” system, which plays a critical role in cell function and survival and consists of two components: molecular chaperones and ubiquitin-proteasome pathway (UPP).[3]
Summary
Protein misfolding is believed to be the primary cause of several neurodegenerative diseases in humans, such as Alzheimer’s disease (AD), Creutzfeldt-Jakob disease, Gaucher’s disease, Huntington’s disease, Parkinson’s disease, Prion’s disease, cystic fibrosis (CF), α1-antitrypsin deficiency, and many others. Over the past few years, a number of factors, such as mutations that destabilize the folded structure (Fig. 1H), changes in the environmental conditions (pH, oxidative stress, and metal ions), and the activity of certain proteins collectively named pathological chaperones (apolipoprotein E, amyloid P component, and protein X), have been identified to play such a critical role.[5] Once a certain concentration of the misfolded protein is reached, the formation of their aggregates can occur in the cells (Fig. 1J and K), leading to the formation of an amyloid-like structure, which eventually causes different types of neurodegenerative disorders and leads to cell death.[3]. After the nucleation or seeding step, the growing assemblies, ordered prefibrillar aggregates or protofibrils (Fig. 1M), are formed via an elongation process and eventually give rise to mature amyloid fibrils.[10]
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