Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.14 (ATP synthase)
7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Subunit c is normally present as an inner mitochondrial membrane component of the F0 sector of the ATP synthase complex, but in the late infantile form of neuronal ceroid-lipofuscinosis (NCL) it was also found in lysosomes in high concentrations. The rate of degradation of subunit c as measured by pulse-chase and immunoprecipitation showed a marked delay of degradation in patients' fibroblasts with late infantile form of NCL. There were no significant differences between control cells and cells with disease in the degradation of cytochrome oxidase subunit IV, an inner membrane protein of mitochondria. Measurement of labeled subunit c in mitochondrial and lysosomal fractions showed that the accumulation of labeled subunit c in the mitochondrial fraction can be detected before lysosomal appearance of radioactive subunit c, suggesting that subunit c accumulated as a consequence of abnormal catabolism in the mitochondrion and is transferred to lysosomes through an autophagic process. The biosynthetic rate of subunit c and mRNA levels for P1 and P2 genes that code for it were almost the same in both control and patient cells. These findings suggest that a specific failure in the degradation of subunit c after its normal inclusion in mitochondria and its consequent accumulation in lysosomes.
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PMID:Abnormal degradative pathway of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid-lipofuscinosis (Batten disease). 766 41

Analysis of storage bodies in the ceroid-lipofuscinoses (Batten disease) has demonstrated a high protein content suggestive of a proteinosis. Direct N-terminal sequencing has shown that subunit c of mitochondrial ATP synthase is specifically stored in the disease in sheep and cattle, and in the human late infantile and juvenile diseases, as well as in 3 breeds of dogs. No differences have been found between the stored subunit c and that in normal mitochondria. No other mitochondrial components are stored. Different proteins, sphingolipid activator proteins (SAPs or saposins) A and D, are stored in the infantile disease. Linkage studies have shown that different forms of ceroid-lipofuscinosis are coded for on different genes on different chromosomes. The genes for subunit c, its production, its insertion into mitochondria, and mitochondrial function are normal. This suggests that underlying the various forms of the disease is a family of lesions in the normal pathway of subunit c turnover, after its normal insertion into the ATP synthase complex. Antibodies to subunit c offer one way of mapping that pathway and detecting the sites of lesions. Specific antibodies have been raised against stored subunit c, using a liposomal adjuvant system which proved superior to classical adjuvants. These antibodies are also useful diagnostically, both in Western blotting and in immunocytochemistry.
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PMID:Batten disease and the ATP synthase subunit c turnover pathway: raising antibodies to subunit c. 766 42

Two-dimensional polyacrylamide gel electrophoresis has been used to search for disease-related protein variation in South Hampshire sheep with ovine ceroid-lipofuscinosis. Several hundred proteins in homogenates and subcellular fractions from livers have been examined, using isoelectric focusing as the first dimension separation, and SDS PAGE in the second dimension. Under these circumstances it was not possible to detect subunit c of the Fo region of ATP synthase, as this protein did not enter the isoelectric focusing gels. However, our studies emphasize the selective nature of misprocessing of subunit c, as we have not been able to detect any other consistent variation between affected and control animals for over 200 mitochondrial fraction proteins. Comparison of the presence or absence, and abundance, of proteins from isolated storage bodies with their counterparts in subcellular fractions from normal liver indicated that storage bodies contained a small subset of mitochondrial proteins, in addition to subunit c, with possible minor contributions from lysosomal, microsomal, and soluble proteins. Analysis of extramitochondrial proteins showed greater than 10-20-fold accumulation of ferritin light chains in microsomes, and partial loss of a putatively lysosomal protein, in ovine ceroid-lipofuscinosis. In addition, senescence marker protein was more abundant in the cytosolic fraction of controls, compared with affected individuals. We are currently investigating the basis and significance of these differences.
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PMID:Variant proteins in ovine ceroid-lipofuscinosis. 766 45

Multiple forms of ceroid-lipofuscinosis occur in human beings and animals. They are characterized by brain and retinal atrophy associated with selective necrosis of neurons. This neurodegenerative disease appears associated with the disease process rather than storage of fluorescent lipopigment per se, and there is now growing evidence that pathogenesis may involve mitochondria rather than a primary defect of lysosomal catabolism. Of the forms of ceroid-lipofuscinosis studied, most but not all reflect accumulation of subunit c of mitochondrial ATP synthase. If there is a common denominator between all forms other than the presence of fluorescent lipopigment, then it may be the accumulation of hydrophobic protein. Analogous diseases in animals can be expected to reflect the same spectrum of biochemical changes, and they warrant in-depth study to help understand the pathogenesis and heterogeneity of the group.
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PMID:Comparative biology of the neuronal ceroid-lipofuscinoses (NCL): an overview. 766 52

Pathological studies of mice homozygous for the motor neuron degeneration (Mnd) mutation show abnormalities similar to those of the human neuronal ceroid lipofuscinoses: sudanophilic, autofluorescent intraneuronal inclusions that are immunoreactive with antibodies to subunit c of mitochondrial ATP synthase. Ultrastructurally, the inclusions have the pentalaminar structure characteristic of some form of human neuronal ceroid lipofuscinosis and of canine and ovine models of neuronal ceroid lipofuscinosis. Similar inclusions are observed in many somatic organs and in the retina, which develops photoreceptor degeneration. This mutation, previously considered a model of amyotrophic lateral sclerosis, may be a useful model for molecular and genetic studies of human neuronal ceroid lipofuscinosis because mice have been well characterized genetically. Since they are inexpensive to breed and maintain, they can also be used to test therapeutic interventions.
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PMID:Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten's disease). 768 55

Subunit c is normally present as an inner mitochondrial membrane component of the F0 section of the ATP synthase complex, but in the late infantile form of neuronal ceroid lipofuscinosis (NCL) it was also found in lysosomes in high concentrations. To explore the mechanism of storage of subunit c, the rates of degradation and synthesis of subunit c were measured in fibroblast cell types from controls and patients with the late infantile form of NCL. The radiolabel from subunit c decreased with time in control cells, whereas no apparent loss of radioactivity of subunit c was found in patients' cells. There were no significant differences between control cells and cells with disease in the degradation of cytochrome oxidase subunit IV, an inner membrane protein of mitochondria. A combination of pulse-chase and subcellular fractionation analysis showed that a delay of intramitochondrial loss from prelabeled subunit c was seen in all diseased cells tested. Lysosomal appearance of labeled subunit c could be detected after chase for more than 1 week and its radioactivities were variable among diseased cell types. The biosynthetic rate of subunit c was almost the same in both control and patient cells. Northern blotting analyses showed that mRNAs for P1 and P2 genes had no significant difference in lengths and amounts between control and patient cells. Results suggest a specific failure in the degradation of subunit c after its normal inclusion in mitochondria and its consequent accumulation in lysosomes. This is the first direct evidence to show a delay of subunit c degradation in the cells from the late infantile form of NCL.
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PMID:Specific delay of degradation of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid lipofuscinosis (Batten disease). 783 67

Certain forms of ceroid lipofuscinosis, a hereditary degenerative disease, are characterized by accumulation of large amounts of subunit c of mitochondrial ATP synthase in lysosomal storage bodies of numerous tissues. The subunit c protein appears to constitute a major fraction of the total storage body protein. In previous studies it was demonstrated that hydrolysates of total storage body protein from affected humans and sheep contain significant amounts of epsilon-N-trimethyllysine (TML). This finding suggested that one or both of the two lysine residues of subunit c might be methylated in the stored form of the protein. The normal subunit c protein from mitochondria does not appear to be methylated. Using a putative canine model for the juvenile form of ceroid lipofuscinosis, analyses were conducted to determine whether lysosomal storage of subunit c was accompanied by lysine methylation of this protein. In affected dogs, as in humans and sheep with hereditary ceroid lipofuscinosis, the storage bodies were found to contain large amounts of subunit c protein, as indicated by polyacrylamide gel electrophoresis and partial amino acid sequence analysis. The subunit c protein partially purified from isolated storage bodies was found to contain lysine and TML in an almost equimolar ratio. Normal subunit c contains 2 lysine residues, one at position 7 and the other at position 43. Removal of the first 7 residues of the partially purified protein through sequential Edman degradation resulted in a dramatic increase in the TML to lysine ratio in the residual protein. This suggests that lysine residue 43 is methylated. Confirmation that residue 43 of the stored protein is TML was obtained by amino acid sequence analysis after cleavage of the protein with trypsin. This finding strongly suggests that specific methylation of lysine residue 43 of mitochondrial ATP synthase plays a central role in the lysosomal storage of this protein.
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PMID:Lysine methylation of mitochondrial ATP synthase subunit c stored in tissues of dogs with hereditary ceroid lipofuscinosis. 814 84

Recent data showed storage of subunit c of mitochondrial ATP synthase in late infantile, juvenile, and adult forms of neuronal ceroid lipofuscinosis (NCL). The present study demonstrates that the expression of subunit c in NCL fibroblasts in long-term cultures, both grown in standard conditions and after leupeptin and ammonium chloride treatment, is not greater than in controls. It indicates that as a result of yet undefined factors, NCL fibroblasts in long-term cultures, lose their ability to accumulate subunit c. Moreover, both Western blot analysis of brain tissue homogenates and immunohistochemistry showed increased immunoreactivity to subunit c in mucopolysaccharidosis type I and III. This increased subunit c expression in a disorder with impaired lysosomal function other than the NCL supports the hypothesis that accumulation of this proteolipid might be related to its defective degradation.
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PMID:Increased expression of subunit c of mitochondrial ATP synthase in brain tissue from neuronal ceroid lipofuscinoses and mucopolysaccharidosis cases but not in long-term fibroblast cultures. 815 85

The human and bovine genomes each contain two expressed nuclear genes, called P1 and P2, for subunit c, a hydrophobic subunit of the membrane sector, Fo, of mitochondrial ATP synthase. Both P1 and P2 encode the same mature protein, but the associated mitochondrial import sequences are different. In sheep with the neurodegenerative disease ceroid lipofuscinosis, and also in humans with Batten's disease, unmodified subunit c accumulates in lysosome-derived organelles in a variety of tissues. However, the sequences of cDNAs for P1 and P2 from sheep with ceroid lipofuscinosis were identical to those in healthy control animals. Therefore, since there was no mutation in either of the mitochondrial import sequences of subunit c in the diseased animals, ceroid lipofuscinosis does not arise from changes in an import sequence causing mis-targeting of the c subunit to lysosomes. The levels of expression of P1 and P2 genes were approximately the same in diseased and healthy animals, and so the protein is unlikely to accumulate because of excessive transcription of either gene. Transcription of a spliced pseudogene related to P2 was detected in both a control animal and a sheep with ceroid lipofuscinosis. The transcripts encode amino acids 1-31 of the P2 mitochondrial targeting sequence. In the diseased animal, an arginine replaced a glutamine in the control sequence. However, restriction fragment analysis of genomic DNA from a further 12 sheep established that the sequence differences were not linked to ceroid lipofuscinosis.
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PMID:Characterization of the expressed genes for subunit c of mitochondrial ATP synthase in sheep with ceroid lipofuscinosis. 832 73

Subunit c is normally present as an inner mitochondrial membrane component of the Fo sector of the ATP synthase complex, but in the late infantile form of neuronal ceroid lipofuscinosis (NCL) it was also found in lysosomes in high concentrations. Mechanism for specific accumulation of subunit c in lysosomes is not known. The rate of degradation of subunit c as measured by pulsechase and immunoprecipitation showed a marked delay of degradation in patients fibroblasts with late infantile form of NCL. There were no significant differences between control cells and cells with disease in the degradation of cytochrome oxidase subunit IV, an inner membrane protein of mitochondria. Measurement of labeled subunit c in mitochondrial and lysosomal fractions showed that the accumulation of labeled subunit c in the mitochondrial fraction can be detected before lysosomal appearance of radioactive subunit c, suggesting that subunit c accumulated as a consequence of abnormal catabolism in the mitochondrion and is transferred to lysosomes, through an autophagic process. There were no large differences of various lysosomal protease activities between control and patient cells. In patient cells sucrose loading caused a marked shift of lysosomal density, but did not a shift of subunit c containing storage body. The biosynthetic rate of subunit c and mRNA levels for P1 and P2 genes that code for it were almost the same in both control and patient cells. These findings suggest that a specific failure in the degradation of subunit c after its normal inclusion in mitochondria and its consequent accumulation in lysosomes.
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PMID:New insight into lysosomal protein storage disease: delayed catabolism of ATP synthase subunit c in Batten disease. 878 16


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