Protein misfolding has interestingly been referred to as the ‘dark side’ of the protein world. The cytotoxicity of misfolded and unfolded polypeptides is due to an overwhelmed quality control system, mainly comprising molecular chaperones to assist in folding, the unfolded protein response (UPR) in the endoplasmic reticulum and the heat shock response (HSR) in the cytosol, which are aimed at clearing misfolded proteins and their early aggregates. When misfolded/unfolded polypeptides exceed the quality control measures of the chaperone–ubiquitin–proteasome clearing system, they form toxic pre-fibrillar aggregates which interact with the cell membrane, disrupting redox potential due to aggregate organization into non-specific membrane pores. In most cases, increases in intracellular free Ca²⁺ and consequent disruption of the redox potential are among the earliest biochemical alterations in exposed cells. An improved understanding of the mechanisms of protein misfolding and intermediate structures that lead from monomers to oligomers ready to aggregate could provide crucial impetus to therapeutic interventions such as upregulating molecular chaperone machinery, use of antibodies and high throughput screening of promising candidate molecules.

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