The ceroid-lipofuscinoses are hereditary neurodegenerative disorders characterized by visual loss, seizures, psychomotor and cognitive deterioration to a vegetative state, and early death. The severe and progressive nature of these diseases result in 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 these disorders is a massive intracellular accumulation of autofluorescent lysosomal storage bodies in most tissues. The accumulation of these inclusions suggests that the ceroid-lipofuscinoses are storage diseases resulting from defects in one or more important metabolic pathways. If this is the case, identifying the chemical contents of the storage bodies ought to provide insight into the etiology of this group of diseases. The subunit c protein of mitochondrial ATP synthase is a major constituent of the storage bodies in two forms of ceroid-lipofuscinosis in humans, and in dogs, sheep, and mice with disorders analogous to one of the human forms. It appears that methylation of specific amino acid residues in subunit c may be involved in its accumulation in lysosomal storage bodies. The overall goals of the proposed research are to determine the mechanisms responsible for the lysosomal storage of methylated forms of subunit c protein, and to determine whether the appearance and progression of the disease symptoms can be impeded by inhibiting Iysosomal storage of the methylated subunit c protein. To accomplish these goals, experiments will be conducted to achieve the following specific aims: (1) determine whether disease-specific urinary peptides found in juvenile ceroid-lipofuscinosis are derived from lysine- methylated proteins; (2) determine whether the accumulation of subunit c in animals and humans with hereditary ceroid-lipofuscinosis could result from a defect in the metabolic conversion of trimethyllysine (TML) to carnitine; (3) determine whether one of the two lysine residues in mitochondrial ATP synthase subunit c is normally methylated; (4) determine whether exposure of cells to free TML inhibits subunit c turnover and results in the accumulation of TML-containing subunit c; (5) determine whether dietary carnitine supplements can slow or halt the progression of disease symptoms in a mouse model for ceroid- lipofuscinosis; and (6) determine whether the S-methylmethionine in the storage body proteins of humans with late infantile ceroid- lipofuscinosis arises as a result of S-methylation of one or more of the methionine residues of the storage body subunit c.
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