Storage protein in hereditary ceroid-lipofuscinosis contains S-methylated methionine

Hereditary ceroid-lipofuscinoses are neurodegenerative disorders characterized by the accumulation in numerous tissues of a storage material with lipofuscin-like fluorescence properties. Investigations were undertaken to determine the chemical nature of this storage material isolated from the cerebral cortex of human subjects with the late infantile form of the disease. The storage material was mainly protein that consisted of a mixture of polypeptides ranging in apparent molecular weight from 13 to 67 kDa. Protein-bound fluorophores apparently were largely responsible for the autofluorescence of the storage bodies. The disease-related storage body protein was rich in S-methylmethionine [(3-amino-3-carboxypropyl) dimethyl sulfonium ion], an amino acid that does not normally occur in animal proteins. Methylation of proteins to form this unusual charged amino acid may impair proteolytic degradation or other aspects of protein metabolism, and account for the accumulation of protein-filled inclusions in cells of individuals with ceroid-lipofuscinoses. Similar amino acid modifications that block proteolysis could be involved in age pigment accumulation.