The Research Problem
There are two predominant issues in amyloid research. The first is the question of the structure and assembly mechanisms of protein aggregates such as the amyloid fibril. The second involves the in vivo mechanisms by which protein aggregates cause disease. A better understanding of both issues will lead to development of diagnostics, for earlier detection of disease, and therapeutics, eradication or slowing the progress of the disease.
Protein Aggregate Structure and Assembly. Proteins are complicated polymers composed of unique, gene-encoded sequences of the twenty amino acids. In order to reach their desired biological destinations and to be functional, proteins have to achieve and maintain very particular folded structures. These folding shapes at one level are dictated by complex directions intrinsic to the amino acid sequence. At the same time, molecular machinery within the cell is responsible for helping the protein realize the shape encoded within its sequence. Defects in the amino acid sequence (that is, mutations), defects in the folding machinery or other cellular systems, or unusual conditions such as infections or other health problems, can all trigger the onset of an aberrant protein aggregation reaction. Such "misfolding" and aggregation reactions are difficult to study, even in the highly simplified, highly idealized situation of a test tube experiment. Many additional levels of complexity are encountered when attempting to understand amyloidogenesis in vivo.
Equally obscure at present is the fundamental structure of any protein aggregate or amyloid fibril. Compared to our knowledge of the structures of other disease-related proteins, such as the HIV protease, at atomic resolution, we have only low resolution impressions of protein aggregate structure. Since technical problems prevent the application of standard techniques for high resolution structure determination to the amyloid structure, there is currently a great interest in developing new methods, as well as revisiting classical methods.
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