INVESTIGATIONS OF AMYLOIDOGENESIS

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Protein deposition diseases have become better understood in recent years. These are diseases where plaque of a type which is termed 'amyloid' forms in a number of organs. This is found to be composed of microscopic filaments or 'fibrils' made out of proteins which are normal constituents of the body. The most well known of these are neurological diseases such as Alzheimer's disease. More recently it has been discovered that Parkinson's disease also falls into this category. Another class of neurological diseases is the encephalopathies such as Creuzfeld-Jacob disease in humans, BSC (or 'mad cow disease') in cattle and scrapie in sheep. Although these are very rare in humans, they are of considerable concern since it has been shown that the proteins involved, so-called 'prions' appear to actually transmit the disease from cows to humans. One of the big mysteries in this kind of disease is understanding how perfectly normal protein constituents of the body start to change in a way that forms these plaques. In the proposed research Dr. Doniach and his colleagues will investigate the molecular basis for formation of amyloid fibrils by studying a number of proteins which are known to be involved in deposition diseases: AL amyloidosis, alpha-synuclein (Parkinson's) and two model systems. In addition to biochemical measurements, they will perform time-resolved small angle x-ray scattering measurements on solutions of the amyloid forming proteins and their mutants in order to study the kinetics of self-association and the size and shape of oligomers formed on the pathway to their formation. The long term aim of this research will be to gain sufficient information about the molecular derails of fibril formation so that eventually it will be possible to design drugs for slowing down or possibly inhibiting the deposition process which is believed to be at the root of this class of disease.