Search PubMed⌕ Search

Biomedical subjects

R D Jolly

Publications and source records attributed to R D Jolly.

At least 55 records · Page 3Linked to original sources
PubMed1995

Batten disease (ceroid-lipofuscinosis): the enigma of subunit c of mitochondrial ATP synthase accumulation.

Ceroid-lipofuscinosis is an inherited neurodegenerative disease of human beings and domestic animals characterized by the accumulation in neurons and other cells of a fluorescent lipopigment. In the ovine form of disease, subunit c of mitochondrial ATP synthase is the dominant accumulated metabolite ( > 50%). It also accumulates significantly in the late infantile and juvenile forms of the human disease and several other animal forms. Evidence is accumulating that the underlying biochemical defect may be associated with mitochondria. The extreme hydrophobicity of subunit c and its propensity to aggregate with lipids into regular multilamellar arrays that cannot be catabolised may reflect an initial defect not necessarily associated with faulty proteolysis. This hypothesis extends an earlier one that subunit c accumulated due to a defect in its catabolic pathway.

Animals↗
PubMed1995

The neuronal ceroid-lipofuscinoses (Batten disease): comparative aspects.

The ceroid-lipofuscinoses are a group of inherited neurodegenerative diseases of human beings characterized by the accumulation of a fluorescent lipopigment in neurons and other cells within the body. There is usually atrophy of both brain and retina with preferential loss of particular neurons. Biochemically, the diseases divide into at least two groups, i.e. those that accumulate subunit c of mitochondrial ATP synthase and those that do not. Dolichol pyrophosphate linked oligosaccharides are also present in storage material. As the underlying biochemical anomalies are not known, the various clinicopathological entities are classified on clinical grounds, by age of onset and, to a lesser extent, by the course of the disease. The best recognized diseases are infantile, late infantile, early juvenile, juvenile and adult onset forms but other variants occur indicating considerable heterogeneity within the group. The infantile, late infantile and juvenile diseases are not allelic. Analogous diseases occur in a variety of animal species. That in the sheep has been extensively studied as a model of the human disease and is the prototype subunit c storage disease.

Animals↗
PubMed1995

Lipofuscin in bovine muscle and brain: a model for studying age pigment.

Pigment of brown atrophy of bovine muscle was interpreted as an exacerbation of age pigment accumulation that also occurred in brain. Isolated muscle pigment was able to be solubilised in LDS/beta-mercaptoethanol and found to be composed mainly of protein and lipid. The widespread "assumptive" hypothesis that age pigment reflects insoluble products of lipid/protein peroxidation is questioned. The methodology described allows for further in-depth analyses to test this and other hypotheses based on alternate models of protease resistant protein/lipid complexes of limited solubility.

Aging↗
PubMed1994

Lipofuscin and abnormalities in colloid in the equine thyroid gland in relation to age.

Lipofuscin accumulation and other histological changes in thyroid tissue, previously reported to be age-related, were studied in 31 horses aged up to 35 years. The number of lipofuscin granules relative to thyrocytes increased from birth to 5 years of age. There was a wide individual variation in the number of lipofuscin granules in thyrocytes in mature horses, but this was not directly related to age. Several abnormalities were identified in thyroid colloid. The prevalence of spherites, lipofuscin granules, nucleated cells and shreds of colloid increased with age, but the prevalence of calcium oxalate crystals, erythrocytes, basophilic zones and solid fragments of colloid did not. In horses younger than 7 years, particularly large lipofuscin granules were found in thyrocytes of a small proportion of follicles which also contained abnormal colloid. Such follicles became more common in older horses without being accompanied by large lipofuscin granules. No correlation was found between granule numbers and frequency of colloid abnormalities. These results cast doubt on the traditional assumption that lipofuscin is indigestible cellular residue, since there was little evidence for excretion of granules. It is postulated that lipofuscin in this tissue may be a normal stage in lysosomal catabolism.

Aging↗
PubMed1994

Generalised ceroid-lipofuscinosis and brown bowel syndrome in Cocker spaniel dogs.

The ceroid-lipofuscinoses comprise a group of inherited storage diseases of human beings and animals that are characterised by progressive neurodegenerative disease and the accumulation within cells of a fluorescent lipopigment. A distinct syndrome occurs in Cocker spaniel dogs in which there is a generalised accumulation of a lipofuscin-like pigment, with such a heavy accumulation in smooth muscle that the intestine and other organs have a brown discolouration. Such discolouration is not observed in other forms of ceroid-lipofuscinosis. Dogs are clinically affected in adulthood and show progressive hind limb paresis, incoordination, and deficient postural reactions and proprioception. Spinal reflexes may be exaggerated. Behavioural or temperament changes, seizures or blindness may occur.

Journal Article↗
PubMed1993

Characterization of the expressed genes for subunit c of mitochondrial ATP synthase in sheep with ceroid lipofuscinosis.

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.

ATP Synthetase Complexes↗
PubMed1993

Lysosomal storage diseases in livestock.

Lysosomal storage diseases may be inherited or acquired. The former are usually inherited as autosomal traits, and heterozygotes may be identified by having enzyme activity levels approximately midway between normal and diseased values. Founder effect, enhanced by widespread acceptance of artificial breeding technologies, has been important in the spread of these genetic diseases in cattle. Acquired storage diseases of importance to livestock most frequently are plant intoxications.

Animals↗
PubMed1992

Mitochondrial ATP synthase subunit c storage in the ceroid-lipofuscinoses (Batten disease).

The ceroid-lipofuscinoses (Batten disease) are neurodegenerative inherited lysosomal storage diseases of children and animals. A common finding is the occurrence of fluorescent storage bodies (lipopigment) in cells. These have been isolated from tissues of affected sheep. Direct protein sequencing established that the major component is identical to the dicyclohexylcarbodiimide (DCCD) reactive proteolipid, subunit c, of mitochondrial ATP synthase and that this protein accounts for at least 50% of the storage body mass. No other mitochondrial components are stored. Direct sequencing of storage bodies isolated from tissues of children with juvenile and late infantile ceroid-lipofuscinosis established that they also contain large amounts of complete and normal subunit c. It is also stored in the disease in cattle and dogs but is not present in storage bodies from the human infantile form. Subunit c is normally found as part of the mitochondrial ATP synthase complex and accounts for 2-4% of the inner mitochondrial membrane protein. Mitochondria from affected sheep contain normal amounts of this protein. The P1 and P2 genes that code for it are normal as are mRNA levels. Oxidative phosphorylation is also normal. These findings suggest that ovine ceroid-lipofuscinosis is caused by a specific failure in the degradation of subunit c after its normal inclusion into mitochondria, and its consequent abnormal accumulation in lysosomes. This implies a unique pathway for subunit c degradation. It is probable that the human late infantile and juvenile diseases and the disease in cattle and dogs involve lesions in the same pathway.

Amino Acid Sequence↗
PubMed1992

Sheep and other animals with ceroid-lipofuscinoses: their relevance to Batten disease.

Distinct pathological and histopathological changes distinguish the ceroid-lipofuscinoses from other storage diseases of humans and animals. These various disease entities likely reflect a variety of mutations of the same gene, or mutations of different genes associated with metabolism of the same or similar substrates. The disease in sheep most closely resembles the juvenile human disease. In it 50% of the lipopigment consists of subunit c of mitochondrial ATP synthase while the remaining constituents are considered normal for a lysosomal derived cytosome. The same subunit c has been shown to be also stored in affected English Setter, Border Collie, and Tibetan Terrier dogs, the Devon cow, and in the late infantile and juvenile human forms of disease but not in the infantile form. Thus it gives a chemical unity to at least some members of the group and allows a major conceptual change in regard to further directions of research.

Animals↗
PubMed1992

Bovine ceroid-lipofuscinosis: pathology of blindness.

Five Devon cattle with suspected ceroid-lipofuscinosis and aged between 19 and 39 months of age were humanely slaughtered and subjected to post-mortem examination. There was severe atrophy of the cerebrum, particularly of the occipital cortex. Microscopy also showed severe atrophy of the retina with complete loss of photoreceptor cells, even in the youngest animal examined. Histopathologically the disease was characterised by accumulation of a fluorescent lipopigment in neurones, including those of the retina and a severe astrocytosis. The disease, which is characterised by the accumulation of subunit c of mitochondrial ATP synthase, is similar to that extensively described in South Hampshire sheep except that the retinal lesions were more severe. In contrast, tremors were not noted in the cattle. The clinical history and similarity to the disease in sheep and other species indicated inheritance was as an autosomal recessive trait.

Journal Article↗
PubMed1991

Bovine ceroid-lipofuscinosis (Batten's disease): the major component stored is the DCCD-reactive proteolipid, subunit C, of mitochondrial ATP synthase.

The ceroid-lipofuscinoses (Batten's disease) are a group of recessively inherited lysosomal storage diseases of children and animals in which there is intracellular accumulation of a fluorescent lipopigment in a wide variety of cells. Lipopigment bodies isolated from pancreas, liver, kidney and brain tissue from a heifer affected with ceroid-lipofuscinosis contained between 55 and 62% protein. A dominant component comigrated on LDS-PAGE with the major low molecular weight protein stored in ovine ceroid-lipofuscinosis. It was identified by amino acid sequence and mass spectroscopy as the full subunit c of mitochondrial ATP synthase, normally found only in the inner mitochondrial membrane, where it is estimated to account for 2-4% of the membrane protein. In pancreatic lipopigment it accounted for at least 40% of the total lipopigment mass and this storage was considered specific to the disease. No other mitochondrial proteins were found in storage bodies. These results are similar to those found in studies on the ovine and the late infantile and juvenile human forms of the disease. It is concluded that bovine ceroid-lipofuscinosis is also a proteolipid proteinosis in which subunit c of mitochondrial ATP synthase is specifically stored in lysosome derived organelles.

Amino Acid Sequence↗
PubMed1990

The sequence of the major protein stored in ovine ceroid lipofuscinosis is identical with that of the dicyclohexylcarbodiimide-reactive proteolipid of mitochondrial ATP synthase.

The ceroid lipofuscinoses are a group of neurodegenerative lysosomal storage diseases of children and animals that are recessively inherited. In diseased individuals fluorescent storage bodies accumulate in a wide variety of cells, including neurons. Previous studies of these bodies isolated from tissues of affected sheep confirmed that the storage occurs in lysosomes, and showed that the storage body is mostly made of a single protein with an apparent molecular mass of 3500 Da with an N-terminal amino acid sequence that is the same as residues 1-40 of the c-subunit (or dicyclohexylcarbodi-imide-reactive proteolipid) of mitochondrial ATP synthase. In the present work we have shown by direct analysis that the stored protein is identical in sequence with the entire c-subunit of mitochondrial ATP synthase, a very hydrophobic protein of 75 amino acid residues. As far as can be detected by the Edman degradation, the stored protein appears not to have been subject to any post-translational modification other than the correct removal of the mitochondrial import sequences that have been shown in other experiments to be present at the N-terminal of its two different precursors. No other protein accumulates in the storage bodies to any significant extent. Taken with studies of the cDNAs for the c-subunit in normal and diseased sheep, these results indicate that the material that is stored in lysosomes of diseased animals has probably entered mitochondria and has been subjected to the proteolytic processing that is associated with mitochondrial import. This implies that the defect that leads to the lysosomal accumulation concerns the degradative pathway of the c-subunit of ATP synthase. An alternative, but less likely, hypothesis is that for some unknown reason the precursors of subunit c are being directly mis-targeted to lysosomes, where they become processed to yield a protein identical with the protein that is normally found in the mitochondrial ATP synthase assembly, and which then accumulates.

Amino Acid Sequence↗
PubMed1990

beta-Mannosidosis in a Salers calf: a new storage disease of cattle.

A storage disease characterised by widespread vacuolation of cells throughout the body was diagnosed in a newborn calf of the Salers breed. Extraction and analyses of water soluble material showed that the storage material was oligosaccharide in nature and was probably derived from the core region of the heterosaccharide moiety of glycoproteins. Glycosidase analyses showed that the disease was due to a deficiency of acidic beta-mannosidase.

Journal Article↗
PubMed1990

Ovine ceroid-lipofuscinosis is a proteolipid proteinosis.

The pathogenesis of the ceroid-lipofuscinoses, inherited storage diseases of children, was studied in an ovine model. This was shown to have clinical and pathological features most in common with the late infantile and juvenile human forms of the disease. The ability to study sequential changes allowed the retinal lesions to be described as a dystrophy of photoreceptor outer segments which preceded loss of the photoreceptor cells. An early decrease in amplitude of the c-wave electroretinograph was attributed to a decrease in the transpigment epithelial component. The decreased a- and b-wave amplitudes were attributed to the changes in and loss of, photoreceptor cells. The chemical components of isolated storage cytosomes were analyzed and shown to consist mostly of protein. Sequence analysis of the dominantly stored protein showed that it was identical to the DCCD reactive proteolipid or subunit c of mitochondrial adenosine triphosphate synthase and that it comprised approximately 50% of storage material. Based on the adage that the dominantly stored species should reflect the underlying biochemical anomaly, it was concluded that it was of pathogenic significance. This highly hydrophobic protein tends to extract with lipids in chloroform/methanol and is thus known as a proteolipid. Some of the remainder of the stored proteins also had this characteristic. It was concluded that ovine ceroid-lipofuscinosis was a proteinosis, more specifically a proteolipid proteinosis and as such it forms the prototype of a new class of storage diseases. Recognition of the nature of the dominantly stored chemical species has helped understanding of a variety of chemical and physical characteristics attributed to the whole pigment.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1989

Analysis of dolichyl pyrophosphoryl oligosaccharides in purified storage cytosomes from ovine ceroid-lipofuscinosis.

Ovine ceroid-lipofuscinosis is an inherited neurodegenerative disorder characterised by the accumulation of storage cytosomes in brain and visceral organs. Phosphorylated dolichol-containing compounds, largely in the form of dolichyl pyrophosphoryl oligosaccharides, have been shown to constitute 1-2% of the dry weight of storage cytosomes isolated from brain and pancreas, and 0.5 and 0.1% respectively of storage cytosomes isolated from liver and kidney. The carbohydrate portion of these glyconjugates in storage cytosomes isolated from brain, pancreas and liver consisted of a series of oligosaccharides of composition Man2-9GlcNAc2, with Man5-8GlcNAc2 predominating. The concentrations of dolichyl pyrophosphoryl oligosaccharides in storage cytosomes from ovine ceroid-lipofuscinosis are much higher than has been reported for endoplasmic reticulum, their normal functional location.

Animals↗
PubMed1989

Ovine ceroid lipofuscinosis. The major lipopigment protein and the lipid-binding subunit of mitochondrial ATP synthase have the same NH2-terminal sequence.

Previous studies on lipopigment isolated from sheep affected with ceroid lipofuscinosis (Batten's disease) showed that the disease is a lysosomal proteinosis, involving specific storage of peptide(s) that migrate in dodecyl sulfate-polyacrylamide gel electrophoresis with an apparent Mr of 3500. This band is the dominant contributor to the lipopigment mass. When purified total lipopigment proteins were loaded onto a protein sequencer, a dominant sequence was found, identical to the NH2 terminus of the lipid-binding subunit of protein translocating mitochondrial ATP synthase. This sequence was determined to 40 residues and a minimum estimate of 40% made for its contribution to the lipopigment protein mass. The full lipid-binding subunit has physical and chemical properties similar to those of the specifically stored low Mr peptide, which may be the full protein or a large NH2-terminal fragment of it. Lipopigments in the human ceroid lipofuscinoses also contain a major component with similar physical and chemical properties. These and previous results indicate that the genetic lesion in ovine ceroid lipofuscinosis causes an abnormal accumulation of this peptide in lysosomes, i.e. the disease is a proteolipid proteinosis, specifically a lysosomal mitochondrial ATP synthase lipid-binding subunit proteinosis. The analogous human diseases are likely to reflect storage of the same or similar peptides.

Animals↗