Neurodegenerative diseases caused by protein aggregation: a phenomenon at the borderline between molecular evolution and ageing

Abstract

A process of protein aggregation that causes intracellular or extracellular accumulation of insoluble protein deposits causes many important neurodegenerative diseases associated with the ageing. The recognition that protein aggregation plays a prominent role in pathogenesis of important pathologies such as Alzheimer’s and Parkinson’s diseases prompted the scientific community to focus on the molecular mechanism of protein aggregation. Many proteins with sophisticated functions can self-aggregate because their folding is complicate and abnormal intermolecular contacts can predominate over the normal intramolecular interactions. The review of biochemical functional and pathogenic implications attributed to α synuclein, Aβ peptide, presenilin and apoE highlights for these proteins a common conformational plasticity and the capacity to adapt their secondary structure to surrounding solvent as well as to the contacted ligands. Their functions are not fully elucidated but there is an elevated number of metabolic pathways in which apparently they are involved as well as they generate functional contact with a remarkable number of other proteins. The mechanism by which α synuclein and Aβ protein make fibrils is an example of conformational plasticity because both these polypeptides can visit a coil or helical structure, but otherwise they convert into a pathogenic β sheet structure highly suitable for polymerisation and fibril formation. The emerging question in the puzzling pathogenic basis of these diseases is if protein aggregation associated with ageing has a role in molecular evolution of the species or if it just represents a calculated drawback.