Protein Aggregation and Deposition: Implications for Ion Channel Formation and Membrane Damage

Abstract

Protein deposition, aggregation, and formation of amyloids are associated with a wide range of pathologies, including several neurodegenerative diseases. Aggregation and deposition are a result of malfunction in protein folding, assembly, and transport, caused by protein mutation and/or changes in the cell environment. The mechanism of protein deposition and aggregation is triggered when the hydrophobic and positively charged regions of the misfolded proteins are exposed. The cells aim to regulate these misfolded and malfunctioning aggregation-prone proteins by degradation mechanisms, e.g., proteosomes, and/or by storing them in specialized compartments, e.g., Russell bodies and aggresomes. During these processes, however, some aggregation-prone protein intermediates are capable of aggregation and forming β-sheet based channels in various negatively charged cellular membranes. Adverse cellular conditions, transitional metals, cellular proteins, and genetic mutations play an important role in the formation and function of these non-intrinsic channels. These channels, which can damage membrane function, are pathologic because they can disrupt the metabolic, ionic, and water homeostasis and distort signal transduction. We propose that different conformations of aggregation-prone proteins could alter cell regulation by modifying several ion transport systems and also by forming heterogeneous ion channels. The changes in membrane transport systems are proposed as early steps in impairing neuronal function preceding fibril formation. We conclude that these changes damage the membrane by compromising its integrity and increasing its ion permeability. This mechanism of membrane damage is a general mechanism that may explain other malfunctioning protein processing-related pathologies. Show more