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)

We have developed a method to deliver hydrophobic proteins such as ATP synthase subunit c and ubiquitin to lysosomes of PMN (polymorphonucleocytes) and fibroblasts. ATP synthase subunit c is stored in the lysosomes of various tissues in late infantile and juvenile forms of neuronal ceriod lipofuscinosis, also called Batten disease (BD). Whether this protein storage is due to an abbreviation in protein or in the lysosomal hydrolases of BD is still not clear. We have sequestered this protein and ubiquitin in the lipid membrane of liposomes. The liposomes coated with autologous heat-aggregated IgG or apolipoprotein E when presented to the PMN and fibroblasts, respectively, accumulated in the lysosomes. Both normal and BD PMN degraded 125I-ubiquitin; the rate of degradation was, however, slower by Batten PMN. These studies indicate that a hydrophobic molecule such as subunit c can be delivered to PMN and fibroblasts, and the sequestered proteins are accessible to lysosomal hydrolases. Therefore, this technique can be used to study the metabolism of highly hydrophobic proteins by lysosomes, especially the biochemical mechanism(s) of subunit c storage in BD.
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PMID:Delivery of liposome-sequestered hydrophobic proteins to lysosomes of normal and Batten disease cells. 903 56

The neuronal ceroid-lipofuscinoses (NCL, Batten disease) are fatal inherited neurodegenerative diseases of children characterized by retinal and brain atrophy and the accumulation of electron-dense storage bodies in cells. Mutations in different genes underlie different major forms. The infantile disease (CLN-1, McKusick 256730) is distinguished by the storage of the sphingolipid activator proteins (SAPs) A and D in distinctive granular osmiophilic deposits (GRODs). This contrasts with the other major forms, where subunit c of mitochondrial ATP synthase is stored in various multilamellar profiles. Ceroid-lipofuscinoses also occur in dogs, including a form in miniature Schnauzers with distinctive granular osmiophilic deposit-like storage bodies. Antisera to SAPs A and D reacted to these storage bodies in situ. The presence of SAP D was confirmed by Western blotting and of SAP A by protein sequencing. Neither subunit c of mitochondrial ATP synthase nor of vacuolar ATPase is stored. This suggests that there are two families of ceroid-lipofuscinoses, the subunit c-storing forms, and those in which SAPs A and D, and perhaps other proteins, accumulate. Further work is required to determine whether other forms with granular osmiophilic deposits belong to the latter class and the genetic relationships between them and the human infantile disease.
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PMID:Accumulation of sphingolipid activator proteins (SAPs) A and D in granular osmiophilic deposits in miniature Schnauzer dogs with ceroid-lipofuscinosis. 906 71

alpha-Mannosidosis of Angus calves was studied both for its veterinary importance and as a model of analogous human lysosomal storage diseases. This study facilitated a similar study in Australia on Swainsona spp. intoxication of livestock in which the toxic principle was shown to be an indolizidine alkaloid, Swainsonine. These genetic and acquired alpha-mannosidoses are compared with beta-mannosidosis. Collectively the study has helped the understanding of the processes of glycosylation and catabolism of glycoproteins. An experiment of nature involving an alpha-mannosidosis chimeric calf born co-twin to a normal calf helped to define the expectations and limitations of bone marrow transplants in this type of storage disease in humans. The inherited ceroid-lipofuscinoses (Batten disease) were studied in an ovine model. Isolation and analyses of the fluorescent accumulated lipopigment denied the dogma of lipid peroxidation current in the 1970s and 1980s. It was shown that in this, and analogous diseases in humans, the dominantly accumulated species was the very hydrophobic protein, subunit c of mitochondrial ATP synthase. Contrary to the adage that this should reflect a disorder of lysosomal proteolysis, there is accumulating evidence that the primary defect resides in mitochondria. Because of its hydrophobic nature, subunit c forms paracrystaline complexes which appear resistant to proteolysis within the lysosomal apparatus.
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PMID:The mannosidoses and ceroid-lipofuscinoses: experimental studies on two types of storage disease. 909 78

Since the discovery of mitochondrial ATP synthase subunit c storage in different forms of neuronal ceroid lipofuscinosis (NCL, Batten disease), it has been found that other hydrophobic proteins also accumulate in different forms. Costorage of subunit c of vacuolar ATPase is observed in "mnd/mnd" mice and in English Setters, Border Collies and Tibetan Terriers. A small amount is stored in the ovine disease and none in the human late-infantile disease. It is a storage body matrix component. An additional 8 kDa component immunoreactive to vacuolar ATPase subunit c antibodies is found in brain-derived storage bodies. The sphingolipid activator proteins, SAPs A and D, are stored in the human infantile disease and a form in Miniature Schnauzer dogs, but neither of the c subunits are. These results suggest two classes of NCL, the subunit c-storing diseases, related by a series of lesions in a subunit c-turnover pathway, and the SAP-storing diseases.
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PMID:Different patterns of hydrophobic protein storage in different forms of neuronal ceroid lipofuscinosis (NCL, Batten disease). 915 21

Immunohistochemical and ultrastructural studies were undertaken to determine whether accumulation of subunit c of mitochondrial ATP synthase could be detected microscopically in fibroblasts cultured from patients with late infantile and with juvenile Batten disease. Cells were grown for five weeks with and without colchicine to inhibit cell division, and were studied grown on slides, as cytospin preparations or as centrifuged pellets. The two different immunohistochemical detection methods used (peroxidase/DAB and immunogoldsilver) gave different results, but neither method indicated any accumulation of subunit c. There was no ultrastructural or electronhistochemical evidence of storage. The published biochemical results which give apparently conflicting evidence of excess amounts of subunit c in cultured fibroblasts can be explained by quantitative differences and sensitivity of the detection methods.
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PMID:Light and electron microscopic studies on subunit c in cultured fibroblasts in late infantile and juvenile Batten disease. 915 24

The Saccharomyces cerevisiae gene BTN1, encodes a 408 amino acid putative integral membrane protein, which is 39% identical and 59% similar to the human Cln3p, whose mutant forms are responsible for Batten's disease and for a diminished degradation of mitochondrial ATPase synthase subunit c. Disruption experiments established that Btn1p is not essential for viability, mitochondrial function, or degradation of mitochondrial ATP synthase in yeast.
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PMID:BTN1, a yeast gene corresponding to the human gene responsible for Batten's disease, is not essential for viability, mitochondrial function, or degradation of mitochondrial ATP synthase. 921 33

We have collected 122 late-infantile neuronal ceroid lipofuscinosis (LINCL, CLN2) and 191 juvenile NCL (JNCL, CLN3) cases, diagnosed on the basis of age-at-onset, clinical symptomatology, and pathological findings and representing the most common forms of NCL in the United States, and Europe. However, careful analysis of available data revealed that about 80% of cases show typical and 20% show atypical clinical course and/or pathological findings and thus, may represent variants of LINCL and JNCL, respectively. Recent progress in the biochemistry and molecular genetics of NCL inclined us to reevaluate these atypical NCL cases. The gene responsible for LINCL has not yet been identified, except for the Finnish variant. Accumulation of subunit c of mitochondrial ATP synthase, to curvilinear profiles, is found in LINCL cases. A novel variant of LINCL, with predominantly granular profiles in the lysosomal storage, as well as normal excretion of subunit c in urine samples, was found in five cases. When the palmitoyle-protein thioesterase (PPT) was studied in these five cases, it was found that the level was deficient, suggesting that they are not LINCL, but the infantile form of neuronal ceroid lipofuscinosis (INCL). Using molecular genetic techniques in the typical JNCL cases, common 1.02 kb deletion to CLN3 was found in 23/27 (homozygotes) and in one allele 4/27 (heterozygotes) in affected pedigrees. In atypical JNCL pedigrees, it was found in 5/16 heterozygotes, while in 1/5 pedigrees, a novel mutation of one atypical JNCL where a single amino acid substitution at 295 E-->K was found in one allele. None of the atypical JNCL cases was homozygote. In atypical JNCL cases where mutation in CLN3 has not been identified (11/16 probands), several possibilities may exist. The phenotype may be caused by a yet undefined mutation in CLN3 or may be due to phenotypically overlapping with other forms of NCL. Pheno/genotypic correlation and the diagnostic difficulties are discussed.
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PMID:Atypical late infantile and juvenile forms of neuronal ceroid lipofuscinosis and their diagnostic difficulties. 937 79

Several neuronal ceroid lipofuscinoses (NCL) show storage of subunit c of mitochondrial ATP synthase. The neurodegenerative process, however, remains obscure. We previously reported a decreased basal ATP synthase activity in fibroblasts from late-infantile NCL (CLN2) and juvenile NCL (CLN3) patients. We have now extended the study of the ATP synthase system to an ovine NCL (a model for the late-infantile NCL variant, CLN6) and the infantile NCL (CLN1). In fibroblasts from healthy sheep, active regulation of ATP synthase in response to cellular energy demand was present similar to human cells: ATP synthase was down-regulated under conditions of anoxia or functional uncoupling and was up-regulated in response to calcium. In fibroblasts from NCL sheep, basal ATP synthase activity was slightly elevated and down-regulation in response to anoxia or uncoupling of mitochondria also occurred. Calcium produced an unexpected down-regulation to 55% of basal activity. Activities of respiratory chain enzymes did not differ between healthy and NCL sheep. In fibroblasts from CLN1 patients, basal ATP synthase activity was reduced and regulation of the enzyme was absent. Activities of respiratory chain complexes II and IV were reduced. The defect of ATP synthase regulation found in fibroblasts from NCL sheep and infantile NCL patients is different from the ATP synthase deficiencies demonstrated in late-infantile and juvenile NCL, but problems of mitochondrial energy production, if also expressed in brain, would be a common feature of several NCL forms. Deficient ATP supply could result in degeneration of neurons, especially in those with high energy requirements.
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PMID:Anomalies of mitochondrial ATP synthase regulation in four different types of neuronal ceroid lipofuscinosis. 1019 Nov 28

The neuronal ceroid lipofuscinoses (NCL, Batten disease) are a group of inherited neurodegenerative storage diseases in children. Mutations in different genes underlie different forms. Subunit c of mitochondrial ATP synthase is specifically stored in autofluorescent bodies in most of them, including a form in sheep. Mature bodies are lysosomal but the initial site of storage is not known, nor is it known how this leads to the characteristic neurodegeneration. Neurons were cultured in serum-free medium from control and affected sheep fetuses at 90 days gestation. They showed positive microtubule-associated protein staining, developed neurites, and had typical neuron morphology. Time-dependent accumulation of subunit c and of fluorescent storage bodies was observed in affected cells by immunocytochemistry and confocal microscopy. A small number of autofluorescent bodies were apparent after 4 days in culture. After 10 days these bodies were more numerous, more intensely autofluorescent, and often larger in size. By 14 and 21 days many neurons were packed with autofluorescent material. These bodies were not seen in control cultures. Immunocytochemistry revealed subunit c-positive storage material only in affected neurons and not in affected glial cells. Confocal microscope analysis, using organelle-specific dyes, demonstrated colocalization of autofluorescent bodies with lysosomes, not with mitochondria. Survival rates of the affected cells were unaffected by the storage body accumulation over a 3-month period. These cultures can now be used to study the mechanism of subunit c accumulation and of neurodegeneration and to test therapeutic possibilities.
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PMID:Disease-specific pathology in neurons cultured from sheep affected with ceroid lipofuscinosis. 1019 Nov 33

Specific storage of mitochondrial ATP synthase subunit c occurs in most forms of Batten disease, including the ovine form, but its relationship to the characteristic neurodegeneration is not clear. Storage occurs in most cell types but only neurons are functionally affected. Neurons were cultured from control and affected sheep. Ewes were superovulated and inseminated, and embryos were collected, frozen, stored, and later transplanted into surrogate dams for gestation at times to suit experimental demands. The optimal fetal age for cultures was investigated, from 50 to 125 days. There were no differences between control and affected embryos in this period of rapid growth. At 50 days brains consist of smooth-surfaced hemispheres and cerebellum with no obvious demarcation between gray and white matter. At 90 days they are like miniature adult brains. From 200 to 600 million viable cells were recovered from each fetus, regardless of age. DMEM/F12 with B27 was the most practical medium tested. Cell viability was not as good in medium containing serum. Treatment of surfaces with polylysine aided neuron adhesion. No developmental or viability differences were observed between normal and affected neuron cultures. At plating out cells were rounded. A day later single process outgrowths began. After 4 days these were over 200 microm and by Day 6 had created a network. Most neurons were bipolar. Neurons from 50 to 90-day old fetuses persisted in culture for over 100 days.
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PMID:In vitro culture of neurons from sheep with Batten disease. 1032 28


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