Protein misfolding and related human diseases: A comprehensive review of toxicity, proteins involved, and current therapeutic strategies

Abstract

Most of the cell's chemical reactions and structural components are facilitated by proteins. But proteins are highly dynamic molecules, where numerous modifications or changes in the cellular environment can affect their native conformational fold leading to protein aggregation. Various stress conditions, such as oxidative stress, mutations and metal toxicity may cause protein misfolding and aggregation by shifting the conformational equilibrium towards more aggregation-prone states. Most of the protein misfolding diseases (PMDs) involve aggregation of protein. We have discussed such proteins like Aβ peptide, α-synuclein, amylin and lysozyme involved in Alzheimer's, Parkinson's, type II diabetes and non-neuropathic systemic amyloidosis respectively. Till date, all advances in PMDs therapeutics help symptomatically but do not prevent the root cause of the disease, i.e., the aggregation of protein involved in the diseases. Current efforts focused on developing therapies for PMDs have employed diverse strategies; repositioning pre-existing drugs as it saves time and money; natural compounds that are touted as potential drug candidates have an advantage of being taken in diet normally and will induce lesser side effects. This review also covers recently developed therapeutic strategies like antisense drugs and disaggregases which has yielded therapeutic agents that have transitioned from preclinical studies into human clinical trials.

Keywords: Amyloid; Amyloid toxicity; Therapeutics.