Protein aggregation and deposition: Implications for ion channel formationand membrane damage

Protein deposition, aggregation, and formation of amyloids are associated w ith a wide range of pathologies, including several neurodegenerative diseas es. Aggregation and deposition are a result of malfunction in protein foldi ng, assembly, and transport, caused by protein mutation and/or changes in t he cell environment. The mechanism of protein deposition and aggregation is triggered when the hydrophobic and positively charged regions of the misfo lded proteins are exposed. The cells aim to regulate these misfolded and ma lfunctioning aggregation-prone proteins by degradation mechanisms, e.g., pr oteosomes, and/or by storing them in specialized compartments, e.g., Russel l bodies and aggresomes. During these processes, however, some aggregation- prone protein intermediates are capable of aggregation and forming P-sheet based channels in various negatively charged cellular membranes. Adverse ce llular conditions, transitional metals, cellular proteins, and genetic muta tions play an important role in the formation and function of these non-int rinsic channels. These channels, which can damage membrane function, are pa thologic because they can disrupt the metabolic, ionic, and water homeostas is and distort signal transduction. We propose that different conformations of aggregation-prone proteins could alter cell regulation by modifying sev eral ion transport systems and also by forming heterogeneous ion channels. The changes in membrane transport systems are proposed as early steps in im pairing neuronal function preceding fibril formation. We conclude that thes e changes damage the membrane by compromising its integrity and increasing its ion permeability. This mechanism of membrane damage is a general mechan ism that may explain other malfunctioning protein processing-related pathol ogies.