Modulation of Cellular Protein Quality Control Pathways Using Small Natural Molecules

Abstract

Eukaryotic cellular system is an extremely successful biological model that has evolved over a very long period of time with a higher success rate and utmost efficiency in its structural arrangement and functioning. It consists of a number of processes that monitor and regulate the intracellular signaling and metabolism. The presence of well-developed subsystems for the maintenance of genomic and proteomic repertoire is one major hallmark that the eukaryotes have achieved. Protein quality control (PQC) system represents a group of subsystems, consisting of molecular chaperones, autophagy, and ubiquitin proteasome system (UPS) that helps in folding, maintenance, and degradation of cellular proteins. Deregulation of these pathways under various kinds of unwanted conditions may cause disruption of natively folded proteins, and accumulation of these aberrant proteins may lead to different types of conformational disorders and sometimes speed up the process of ageing. In the past few years, several types of therapeutic strategies have been proposed and worked out by multiple research groups to modulate the efficiency of the PQC pathways, in order to reduce the cellular burden of proteotoxicity. Using small molecules to reestablish the folding efficiency of molecular chaperones and for the upregulation of proteolytic abilities of the UPS and autophagic pathways is one highly worked out and effective approach to provide symptomatic relief in many disease conditions. These small molecules have also shown beneficial effects in interfering with the aggregation pathways of proteins and hence could be used as a possible therapeutic strategy to prevent and cure neurodegeneration and several ageing-associated problems.