The ceroid-lipofuscinoses are a group of inherited diseases characterized by visual loss, seizures, psychomotor and cognitive deterioration, and early death. In the most common form of the disease, the symptoms first appear in early childhood and progress over a period of years to a stage at which the affected individuals become vegetative. The protracted course of the disease produces enormous medical, financial and emotional burdens on families with afflicted children. Little is known regarding the etiology of this group of diseases, and no effective treatments have been developed. A unifying feature of the ceroid-lipofuscinoses is a massive intracellular accumulation of an autofluorescent pigment in most tissues. The accumulation of these cellular inclusions suggest that ceroid-lipofuscinosis is a storage disease resulting from a defect in an important metabolic pathway. If this is a case, determination of the chemical composition of the storage bodies ought to provide insight into the etiology of this group of diseases. It has been reported that the major constituent of the storage bodies in human ceroid-lipofuscinosis, as well as in analogous disorders in sheep and dogs, is protein. The major stored protein in all tissues appears to be a normal mitochondrial constituent. Unlike most normal proteins, however, the storage protein appears to be rich in the modified amino acid epsilon-N-trimethyllysine in dogs, sheep, and humans with the juvenile form of the disease. The overall goal of the proposed research is to determine how the accumulation of protein containing this modified amino acid might be involved in the etiology of the human juvenile form of ceroid- lipofuscinosis. To accomplish this goal, experiments will be performed to achieve the following specific aims: (1) Confirm that the modified amino acid epsilon-N-trimethyllysine occurs in the storage body protein from all tissues of affected dogs, sheep, and humans; (2) Identify the storage body proteins that are the sources of the modified amino acid; (3) Sequence the storage body proteins to determine which residues are modified, and to further characterize the stored protein; (4) Determine whether any proteins are enzymatically methylated in tissues from dogs with ceroid-lipofuscinosis that are not methylated in tissues from normal dogs; (5) Determine whether tissues from affected animals are defective in their ability to demethylate or degrade methylated protein substrates; and (6) Determine whether carnitine synthesis from methylated proteins is altered in affected animals and humans.
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