Proteostasis defects: Medicinal challenges of imperfect aging & neurodegeneration

Abstract

A prolonged healthy life is based on the optimal activity of an organism’s organ systems, and healthy cells are at the core of this proper functioning. Cellular homeostasis is of utmost importance, and a cell deploys several cytoprotective mechanisms to maintain this balance. One such mechanism is protein quality control (PQC) to preserve proteostasis and maintain functionality of proteins. In PQC, the chaperone system and proteolytic pathways like autophagy and ubiquitin-proteasome system (UPS) are primary cell devices preventing misfolding/aggregation of proteins and clearing out toxic protein aggregates and dysfunctional organelles. Aging is an unavoidable biological phenomenon observed in many organisms that negatively affects the functionality of multiple organs systems, thus reducing the life span. It constitutes a significant risk factor for impairment of PQC elements and proteostasis disruption, linked with physiological dysfunction of organelles along with other anomalies. Aging presents various medicinal challenges as it affects multiple physiological processes at once. In aging, declined PQC capacity can lead to increased incidence of several age-associated diseases, including neurodegenerative disorders. Proper maintenance and modulation of these PQC elements present an attractive therapeutic intervention opportunity for such disorders. Here, we present PQC and its components as a system affected in imperfect aging, its potential for modulation to improve healthspan and counter aging associated disorders, along with challenges linked with inherent complex nature of aging biology.

Keywords

• Chaperones
• Proteasome
• E3 ubiquitin ligases
• Autophagy
• Aging
• Neurodegeneration