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)

Mechanism of lysosomal storage of mitochondrial ATP synthase subunit c in late infantile form of NCL was studied. Morphological and biochemical examinations with patient fibroblasts showed that subunit c, not other mitochondrial proteins was specifically localized in lysosomes. 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. Measurement of labeled subunit c in mitochondrial and lysosomal fractions showed a specific delay of degradation of subunit c in patient cells with late infantile form of NCL and lysosomal transfer of radioactive mitochondrial subunit c after chase for 1-2 weeks, suggesting that subunit c is transfered to lysosomes through an autophagic process and accumulated as a consequence of abnormal catabolism in lysosomes.
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PMID:Defect of proteolysis of mitochondrial ATP synthase subunit C in neuronal ceroid lipofuscinosis. 882 37

The tissues from three patients with late-infantile NCL originally described by Max Bielschowsky became available to apply modern techniques such as fluorescence microscopy, electron microscopy and immunohistochemistry. While regular tinctorial preparations of the tissues documented a neuronal storage disorder in all three patients' tissues, the accumulated material proved to be autofluorescent, showed the ultrastructure of curvilinear lipopigments, and reacted strongly with an antibody against the subunit-C of mitochondrial ATP synthase, a major component of lipopigments in NCL and also with an antibody against sphingolipid activator proteins. Thus, these modern morphological techniques demonstrated that the originally described three siblings with late-infantile "amaurotic familial idiocy" really had neuronal ceroid-lipofuscinosis of the late-infantile or Jansky-Bielschowsky type, according to current diagnostic criteria. This type of archival study may also contribute to the mosaic of medical history.
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PMID:Neuronal ceroid-lipofuscinosis--late-infantile or Jansky-Bielschowsky type--revisited. 886 79

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

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

Development of the ovine model of NCL has been pivotal to our present understanding of the ceroid lipofuscinoses. Analyses of isolated storage product have shown it to be composed of identifiable chemical species of which subunit c of mitochondrial ATP synthase is dominant (ca 50%). It is an extremely hydrophobic protein and failure to catabolise it may be associated with a propensity to form paracrystalline structures with lipids that cannot be degraded by the normal complement of lysosomal enzymes. However, the putative biochemical defect must be related to it and may reside within the mitochondria. Multiple copies of subunit c help form the transmembrane Fo complex which, with partially immobilised lipids, forms an Fo complex domain. This may need to be disassembled in an orderly fashion before proteolysis of subunit c can occur. It is postulated that the primary defect may involve disassembly of the Fo complex domain which may involve more than one step.
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PMID:The ovine model of neuronal ceroid lipofuscinosis (NCL): its contribution to understanding the pathogenesis of Batten disease. 915 25

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

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

Neuronal ceroid lipofuscinoses represent a group of diseases which has until quite recently resisted definite elucidation of the underlying defect(s) on the molecular level. The common feature of all the NCLs is a serious and progressive neurological disorder, accompanied, with only few exceptions, by retinal degeneration. Visceral symptoms, despite the presence of the storage process, are absent, or minimal. There are many clinical variants of the disease process, among which a set of standard, historical phenotypes exists found to be linked to specific genotypes. The disorder is inherited and transmitted as an autosomal recessive trait. At the cellular level, it is featured by lyzosomal storage of autofluorescent hydrophobic material, the substantial part of which consists of hydrophobic proteins and esterified dolichol. The dominant protein is the subunit c of mitochondria ATP synthase. In one NCL type (NCL1) the dominant proteins are saposins A and D. Ultrastructural appearance is membranous with several relatively specific patterns with some tendency to condensation or, namely in NCL3 to vacuolar distension. Amorphous appearance is associated with NCL1. The impact of the disease process on the cell biology differs substantially depending on the cell type. The brain neurons are most seriously affected and degenerate, whereas other cell types mostly survive without detectable deterioration. Pathogenesis at the molecular level is now being elucidated using the modern molecular biology techniques, which have already enabled unravelling of a set of genes controlling majority of the standard historical phenotypes. The original infantile form of NCL (NCL1) is now defined as palmitoyl protein thioesterase deficiency (gen at the 1p32 locus), the late infantile form (NCL2) as pepstatin resistant proteinase deficiency (gen at the 11p15.5 locus) and the original juvenile form (NCL3) as a defect of the specific gene (locus 16p11.2-12.3), the product of which, the NCL3 protein, still lacks functional characterization. Two gene loci have been identified in the so-called early juvenile, or variant late infantile NCL. One of them is in the 13q21 locus (NCL5 or Finnish variant late infantile form), the second is in the 15q21-23 one (NCL6). Kufs form remains the least defined form of NCL. Recently two novel NCL variants were described with specific loci. Thanks to introduction of molecular genetic based diagnosis it was possible to recognize, besides the standard phenotype, existence of further phenotypic variants. The phenotype based scheme of NCL has thus been definitely substituted by classification based on genotype and biochemistry.
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PMID:[Neuronal ceroid lipofuscinosis. Closing chapter of a long story]. 1091 28

The specific accumulation of a hydrophobic protein, subunit c of ATP synthase, in lysosomes from the cells of patients with the late infantile form of NCL (LINCL) is caused by a defect in the CLN2 gene product, tripeptidyl peptidase I (TPP-I). The data here show that TPP-I is involved in the initial degradation of subunit c in lysosomes and suggest that its absence leads directly to the lysosomal accumulation of subunit c. The inclusion of a specific inhibitor of TPP-I, Ala-Ala-Phe-chloromethylketone (AAF-CMK), in the culture medium of normal fibroblasts induced the lysosomal accumulation of subunit c. In an in vitro incubation experiment the addition of AAF-CMK to mitochondrial-lysosomal fractions from normal cells inhibited the proteolysis of subunit c, but not the b-subunit of ATP synthase. The use of two antibodies that recognize the aminoterminal and the middle portion of subunit c revealed that the subunit underwent aminoterminal proteolysis, when TPP-I, purified from rat spleen, was added to the mitochondrial fractions. The addition of both purified TPP-I and the soluble lysosomal fractions, which contain various proteinases, to the mitochondrial fractions resulted in rapid degradation of the entire molecule of subunit c, whereas the degradation of subunit c was markedly delayed through the specific inhibition of TPP-I in lysosomal extracts by AAF-CMK. The stable subunit c in the mitochondrial-lysosomal fractions from cells of a patient with LINCL was degraded on incubation with purified TPP-I. The presence of TPP-I led to the sequential cleavage of tripeptides from the N-terminus of the peptide corresponding to the amino terminal sequence of subunit c.
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PMID:Tripeptidyl peptidase I, the late infantile neuronal ceroid lipofuscinosis gene product, initiates the lysosomal degradation of subunit c of ATP synthase. 1096 52

Finland and the Finns have been the subject of numerous genetic and genealogical studies, owing to enrichment of certain rare hereditary disorders in the Finnish population. Two types of NCL have so-far been found almost exclusively in Finland: Finnish variant late infantile NCL, vLINCL (CLN5), and the Northern epilepsy syndrome or Progressive epilepsy with mental retardation, EPMR (CLN8). The first symptoms of Finnish vLINCL are concentration problems or motor clumsiness by 3 to 6 years of age, followed by mental retardation, visual failure, ataxia, myoclonus, and epilepsy. Northern epilepsy, the newest member of the NCL family with the most protracted course, is characterized by the onset of generalized seizures between 5 and 10 years of age and subsequent progressive mental retardation. Visual problems are slight and late, while myoclonus has not been observed. Both the Finnish vLINCL and Northern epilepsy are pathologically characterized by intraneuronal cytoplasmic deposits of autofluorescent granules which are Luxol fast blue-, PAS-, and Sudan black B-positive in paraffin sections. In Northern epilepsy the intraneuronal storage process and neuronal destruction are generally of mild degree but highly selective and, in contrast to other forms of childhood onset NCL, the cerebellar cortex is relatively spared. By electron microscopy the storage bodies mainly contain rectilinear complex type and fingerprint profiles in Finnish vLINCL and structures resembling curvilinear profiles in Northern epilepsy. Mitochondrial ATP synthase subunit c is the main stored protein in both disorders. Both the DCLN5 and CLN8 genes encode putative membrane proteins with yet unknown functions. Furthermore, a well studied spontaneously occurring autosomal recessive mouse mutant, motor neuron degeneration (mnd) mouse, is a homolog for CLN8.
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PMID:Studies of homogenous populations: CLN5 and CLN8. 1133 69


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