Mechanical stress and formation of protein aggregates in neurodegenerative disorders

Abstract

Misfolded protein aggregates and inclusion bodies have been associated with various protein conformation disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and prion diseases including bovine spongiform encephalopathy (BSE). Models have been proposed as plausible explanations for the extension and progression of protein aggregates; however, little is known about the initiation process of protein aggregation, particularly in sporadic neurodegenerative diseases. Epidemiological data have suggested a tight association between sporadic neurodegenerative diseases and history of mechanical stresses such as trauma, head injury, and occupational exposures, including professional soccer and boxer's brain that carries histological hallmarks of AD/PD. Here, we propose that mechanical stress is an environmental factor that provokes a disturbance in cellular quality control systems and molecular chaperones that target misfolded proteins. This subsequently initiates protein aggregation and results in sporadic neurodegenerative disorders. Further, continuous and repetitive exposure to environmental mechanical stress, mostly in an unrecognized manner, is inevitable in daily life and thus, it functions as a potential driving force for protein aggregation. In this regard, a recent identification of the fact that an intracellular mechanosensor actually exists may support our notion. Reduction in the mechanical stress in combination with other conventional aspects should facilitate the development of rational therapeutics for these neurodegenerative disorders.