| It is proposed that the presence of defective amino acid residues in proteins induces structural changes that may lead to alterations of physiological and biochemical properties. If these structural alterations occur in human brain proteins, they may be a factor in the development of such disorders as Alzheimer disease and multiple sclerosis.; The defective amino acids studied in this project were D-aspartate, formed by racemization of the commonly found L-aspartate, and L-iso-aspartate, produced by isomerization of the peptide bond to the {dollar}beta{dollar}-carboxylic group. The main goal of the work presented in this thesis was to determine the location and quantity of defective aspartyl residues in human brain proteins and their possible involvement in neurological disorders.; One of the most significant findings of this program was the discovery that Alzheimer neurofibrillary tangle proteins contained on the average twice as many defective aspartyl residues as found in control gray matter samples. This is the first known example indicating that defective aspartyl residues may be implicated in neurological disorders.; A study of normal human brains to determine the specific location of defective aspartyl residues revealed that myelin basic protein (one of the components of white matter) contained the highest levels of defective aspartate of any sample studied. This finding probably reflects the stability of the myelin basic protein as well as its resistance to any possible enzyme repair mechanism for defective aspartate removal. |
