OO078 - CONCENTRIC BETA BARREL MODELS OF ALPHA SYNUCLEIN, AMYLOID BETA, AND IAPP (ID 1421)
Abstract
Aims
The major objective of analyzing amyloid structures is to develop effective ways to prevent, treat, and/or cure the devastating diseases they cause. Amyloid beta (Aβ) of Alzheimer’s disease, α-synuclein of Parkinson’s disease, and Amylin (IAPP) of Type 2 Diabetes form large fibrils. Evidence is increasing however that much smaller oligomers are more toxic and that these oligomers can form toxic transmembrane ion channels.
Methods
The quest to determine structures of these smaller assemblies can appear hopeless. Amyloid peptides are shapeshifters; they assume countless forms that are often present simultaneously and likely have partially occupied secondary structures. Numerous factors affect Aβ assemblies; e.g., ions and heavy cations, lipids, fatty acids, concentration, time, method of isolation and preparation, location in the body, initial seed conformation, length of the peptide, mutations, and oxidation. Also, they appear to interact with multiple receptors, and with other amyloids. A potential saving grace is that symmetric β-barrels often have well defined structures.
Results
Our models of numerous oligomers, annular protofibrils, lipoprotein complexes, and transmembrane channels contain symmetric β-barrels in which all monomers have identical conformations. These models are consistent with well-established β-barrel theory, molecular modeling principals, and experimental data, including microscopic images.
Conclusions
Hypothetical models and concepts are vital for research because they may suggest experiments that otherwise would not be performed or funded. These experiments include methods: to test aspects of the models, to reduce polymorphism and disorder so that specific structures can be solved experimentally, and to identify specific segments to target for drug and antibody treatments.
