Glycating conditions affect aggregation and toxicity of amyloidogenic peptides

Proteins show an intrinsic propensity to misfolding that is influenced by the amino acid composition, and can be accelerated by certain environmental conditions such as increased temperature, high or low pH, agitation, oxidative agents, transition metals, or elevated glucose. Glycation is the well-described non-enzymatic Maillard reaction of reducing sugars with protein side chains, lipids, or nucleic acids to form Schiff base. Complex multistep reactions and rearrangements during long-term incubation produce various compounds termed advanced glycation end products (AGEs). AGEs were found to induce conformational changes especially to long-living proteins. This contributes to the onset of several diseases, including diabetic complications, renal failure, inflammation, atherosclerosis, cancer, neurodegenerative disorders and more generally age related diseases. AGEs can be recognized by the multiligand receptor for AGEs (RAGE) that has been therefore implicated in the pathogenesis of such diseases. Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases show common cellular and molecular mechanisms including protein misfolding and aggregation, a process termed amyloidogenesis. The amyloid aggregates usually consist of elongated, unbranched protein fibrils deposits containing misfolded proteins with a beta-sheet conformation, and represent the end stage of a molecular cascade of several steps. Increasing evidences now support the view that spontaneous aggregation into small soluble oligomeric (protofibrillar) assemblies during earlier steps, is more directly tied to pathogenesis than the insoluble deposits themselves. Consequently, there is current emphasis in understanding the microenvironmental conditions that favour the initial oligomerization. Glycation plays a prominent role in the conversion of a protein from its native structure to the amyloid and toxic state. This process can be accelerated by free radicals and certain transition metals, particularly Cu(II) and Zn(II). Toxic activity is enhanced by the interaction with RAGE, that functions as a signal transducer for cell impairment. A full understanding of the mechanism of protein misfolding and cross-linking as well as specific receptor signalling is helpful in designing new pharmacological/chemical tools against amyloidogenesis and related diseases.