Abstract
Proteins synthesized in living cells often fail to properly fold, and misfolded proteins are potentially toxic to cells due to the existence of exposed hydrophobic surfaces. For example, misfolded proteins tend to aggregate each other and capture other normal proteins into aggregates. Genetic mutations often cause protein misfolding, and these mutations induce neuronal cell death in neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, polyglutamine disease and amyotrophic lateral sclerosis). However, how misfolded proteins exert cytotoxicity is poorly understood. In living cells, there are two strategies to prevent the toxicity of misfolded proteins: one is prevention of aggregation by molecular chaperones and the other is degradation by proteases. These two systems coordinately monitor quality of proteins and decide the fate of proteins (e.g., reuse after refolding or destruction by protease digestion). We have used aggregation-prone proteins tagged with green fluorescent proteins and derivatives to analyze the dynamics of cytotoxic misfolded proteins in living cells. We discuss how fluorescently labeled proteins are useful to understand the dynamics of misfolded proteins, particularly for those causing neurodegenerative diseases. We also discuss kinetics of interaction between misfolded proteins and binding proteins like molecular chaperones.
