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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS030155-04A2
Application #
2268221
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1991-09-30
Project End
1998-08-31
Budget Start
1995-09-30
Budget End
1996-08-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211
Katz, M L; Shibuya, H; Johnson, G S (2001) Animal models for the ceroid lipofuscinoses. Adv Genet 45:183-203
Riis, R C; Jackson, C; Rebhun, W et al. (1999) Ocular manifestations of equine motor neuron disease. Equine Vet J 31:99-110
Katz, M L; Shibuya, H; Liu, P C et al. (1999) A mouse gene knockout model for juvenile ceroid-lipofuscinosis (Batten disease). J Neurosci Res 57:551-6
Katz, M L; Liu, P C; Grob-Nunn, S E et al. (1999) Characterization and chromosomal mapping of a mouse ortholog of the late-infantile ceroid-lipofuscinosis gene CLN2. Mamm Genome 10:1050-3
Liu, P C; Chen, Y W; Shibuya, H et al. (1998) A polymorphic (GA)n microsatellite in an intron of the canine endothelin-B receptor gene. Anim Genet 29:236
Siakotos, A N; Blair, P S; Savill, J D et al. (1998) Altered mitochondrial function in canine ceroid-lipofuscinosis. Neurochem Res 23:983-9
Shibuya, H; Liu, P C; Katz, M L et al. (1998) Coding sequence and exon/intron organization of the canine CLN3 (Batten disease) gene and its exclusion as the locus for ceroid-lipofuscinosis in English setter dogs. J Neurosci Res 52:268-75
Liu, P C; Shibuya, H; Katz, M L et al. (1998) A BsmFI PCR/RFLP in the canine CD19 gene. Anim Genet 29:64-5
Liu, P C; Chen, Y W; Shibuya, H et al. (1998) Length polymorphism in a CT-rich microsatellite in an intron of the canine tyrosinase-related protein-2 gene. Anim Genet 29:327
Liu, P C; Shibuya, H; Nonneman, D et al. (1998) A BseRI PCR/RFLP in an intron of the canine phenol sulfotransferase gene. Anim Genet 29:329

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