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Biomedical subjects

R D Jolly

Publications and source records attributed to R D Jolly.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mucopolysaccharidosis IIIA (Sanfilippo syndrome) in a New Zealand Huntaway dog with ataxia.

AIM: To investigate the nature of a progressive ataxia in a New Zealand Huntaway dog. METHODS: The affected dog was examined clinically before being humanely killed and necropsied. Selected tissues were submitted to light and electron microscopy and to biochemical analyses. RESULTS: The histological lesions were interpreted as indicative of one of the forms of mucopolysaccharidosis type-III (MPS-III), a lysosomal storage disease. Biochemically there was a deficiency of heparan sulphamidase. All the heparan sulphate chains had non-reducing-end glucosamine-N-sulphate residues. CONCLUSION: The disease is MPS-IIIA (Sanfilippo syndrome). An autosomal recessive mode of inheritance can be provisionally assumed from the nature of this disease in other species.

Journal Article↗
PubMed2000

Progressive myelopathy and neuropathy in New Zealand Huntaway dogs.

AIM: To investigate the nature and cause of a progressive ataxia in three 20-month-old Huntaway dogs that were litter mates. METHODS: Affected dogs were examined before they were humanely killed and submitted to necropsy. Selected formalin-fixed tissues were examined by light and electron microscopy. RESULTS: The lesions were those of axon and myelin degeneration within sensory, proprioceptive and motor tracts of the spinal cord and to a lesser degree some peripheral nerves. CONCLUSION: A progressive myelopathy and neuropathy, tentatively described as a central-peripheral distal axonopathy, was present in all 3 dogs. The cause was not determined but was likely to be either genetic or nutritional. CLINICAL RELEVANCE: In the early stages of this disease, careful examination may be necessary to distinguish the signs of ataxia from orthopaedic disease such as hip dysplasia. Affected animals are unlikely to be of use as working dogs.

Journal Article↗
PubMed1999

Anomalies of mitochondrial ATP synthase regulation in four different types of neuronal ceroid lipofuscinosis.

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.

Animals↗
PubMed1999

Ovine ceroid lipofuscinosis (OCL6): postulated mechanism of neurodegeneration.

It is proposed that ceroid lipofuscinosis in Southhampshire sheep (OCLSouthhampshire) be also known as OCL6 as it is syntenic with CLN6 of humans. Histopathological studies show a severe and progressive neurodegeneration of the cerebral cortex which sometimes appears to have a laminar pattern and which is accompanied by a severe midcortical astrocytosis. Other studies have shown that fibroblasts maintained in tissue culture have abnormal regulation of ATP synthase. If this was reflected in neurons, then selective neuron death is likely to be the result of energy-linked excitotoxicity of neurons receiving abundant glutamate input. Increased sensitivity of the NMDA receptor due to inefficient repolarization of the neuron membrane would allow increased cellular uptake of calcium, increased formation of free radicals, and neuron death. The general hypothesis, as developed for other chronic neurodegenerative diseases, is partly based on application of various drugs that block or mediate parts of the pathway involved. The same approach could be used to help test the hypothesis in OCL6 lambs and if successful some of the drugs might have therapeutic potential. As patterns of neurodegeneration are similar in various other forms of ceroid lipofuscinosis accumulating subunit c of mitochondrial ATP synthase, the model may have more general application than merely to CLN6.

Age Factors↗
PubMed1999

A lower motor neuron disease in newborn Romney lambs.

AIM: To determine the cause and nature of a disease in newborn New Zealand Romney lambs characterised by progressive weakness and premature death. METHODS: Affected lambs were examined clinically, humanely killed and submitted to necropsy. Selected fonmalin-fixed tissues were examined histologically. Data on the parentage of the lambs were collected. RESULTS: The principle lesions found were degeneration and loss of neurons in ventral horns of the spinal cord and brain stem and Wallerian degeneration of motor nerves and denervation atrophy of skeletal muscles fibres. CONCLUSION: The lesions are those of a lower motor neuron disease which appeared to have a genetic cause.

Journal Article↗
PubMed1998

Ovine neuronal ceroid lipofuscinosis: a large animal model syntenic with the human neuronal ceroid lipofuscinosis variant CLN6.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited degenerative neurological diseases affecting children. A number of non-allelic variants have been identified within the human population and the genes for some of these have recently been identified. The underlying mechanism for the neuropathology remains an enigma; however, pioneering studies with the naturally occurring ovine model (OCL) have led to the proposal that these diseases represent lesions in specific hydrophobic protein degradation pathways. In this study, we show linkage between OCL and microsatellite markers on OAR 7q13-15. Using interspecies chromosome painting we establish that OAR 7q13-15 is syntenic with human chromosome 15q21-23, the region which was recently defined as the location of a newly identified late infantile variant (CLN6). We propose that our ovine model represents a mutation in the gene orthologous to that mutated in the human late infantile variant CLN6. The ovine linkage flock, consisting of 56 families, represents a powerful resource for positional cloning of this NCL gene. The availability of such a large animal model will have important implications for experimentation in downstream corrective therapies.

Age of Onset↗
PubMed1997

Accumulation of sphingolipid activator proteins (SAPs) A and D in granular osmiophilic deposits in miniature Schnauzer dogs with ceroid-lipofuscinosis.

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.

Animals↗
PubMed1997

Different patterns of hydrophobic protein storage in different forms of neuronal ceroid lipofuscinosis (NCL, Batten disease).

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.

ATP Synthetase Complexes↗
PubMed1997

The ovine model of neuronal ceroid lipofuscinosis (NCL): its contribution to understanding the pathogenesis of Batten disease.

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.

ATP Synthetase Complexes↗
PubMed1997

The mannosidoses and ceroid-lipofuscinoses: experimental studies on two types of storage disease.

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.

Animals↗
PubMed1997

Lysosomal storage diseases of animals: an essay in comparative pathology.

A wide variety of inherited lysosomal hydrolase deficiencies have been reported in animals and are characterized by accumulation of sphingolipids, glycolipids, oligosaccharides, or mucopolysaccharides within lysosomes. Inhibitors of a lysosomal hydrolase, e.g., swainsonine, may also induce storage disease. Another group of lysosomal storage diseases, the ceroid-lipofuscinoses, involve the accumulation of hydrophobic proteins, but their pathogenesis is unclear. Some of these diseases are of veterinary importance, and those caused by a hydrolase deficiency can be controlled by detection of heterozygotes through the gene dosage phenomenon or by molecular genetic techniques. Other of these diseases are important to biomedical research either as models of the analogous human disease and/or through their ability to help elucidate specific aspects of cell biology. Some of these models have been used to explore possible therapeutic strategies and to define their limitations and expectations.

Animal Diseases↗
PubMed1996

Apoptosis as the mechanism of neurodegeneration in Batten's disease.

Batten's disease is a genetic neurodegenerative disease of childhood. Its hallmarks are retinitis pigmentosa and neuronal degeneration. As some types of photoreceptor death in mice are mediated by apoptosis, we investigated whether apoptosis is responsible for retinal and neuronal degeneration in the late infantile and juvenile forms of Batten's disease. Using the terminal dUDP nick end-labeling (TUNEL) staining method, we detected apoptotic neuronal cells in brain from patients and a canine model and in brain and retina from an ovine model for Batten's disease. We confirmed apoptosis by flow cytometry, electron microscopy, and DNA laddering. This is the first inherited neurodegenerative disease involving brain and retina in which apoptosis has been established as the mechanism of neuronal and photoreceptor cell death in both humans and animal models.

Animals↗
PubMed1995

Immunocytochemical studies in the ceroid-lipofuscinoses (Batten disease) using antibodies to subunit c of mitochondrial ATP synthase.

Immunocytochemistry, using antibodies against subunit c of mitochondrial ATP synthase, has been carried out in the ovine, canine, late infantile, and adult forms of ceroid-lipofuscinosis. Intensity of staining varied depending on the particular disease, species, fixation regime, and the antibody used. Differential staining of storage cytosomes in neurons of affected sheep and those in the late infantile patient suggested exposure of different epitopes. This was supported by the variable staining using two different antibodies in ovine, late infantile, and adult onset (Kufs) diseases. Immunostaining of muscle in the late infantile, and muscle and ear cartilage in affected sheep can assist diagnosis but positive results may depend on the age of the patient, at least in the latter species. In these tissues there was immunostaining of structures not identified by histochemical or fluorescence microscopy in addition to storage cytosomes that could be identified by these means. Poor or no immunostaining occurred with canine tissues. At the ultrastructural level, storage cytosomes but not other organelles stained with the immunogold method.

Adult↗
PubMed1995

Pathogenesis of brain dysfunction in Batten disease.

Animal models of Batten disease and other neuronal storage disorders offer important opportunities to study the pathogenesis of brain dysfunction in this family of diseases. Although all of these conditions exhibit progressive intraneuronal storage, we have found that other aspects of the cellular pathology of Batten disease differ markedly from those of storage disorders caused by lysosomal hydrolase deficiencies. Likewise, lysosomal of cerebral cortex and other select brain regions, a prominent characteristic of Batten disease, does not occur in most other storage disorders. Our studies indicate that Batten disease has findings in common with human neurodegenerative diseases and that neuron death may be caused by excitotoxicity occurring secondary to the combined effects of suboptimal mitochondrial function and GABAergic (inhibitory) cell loss.

Animals↗
PubMed1995

Variant proteins in ovine ceroid-lipofuscinosis.

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.

Animals↗
PubMed1995

Comparative biology of the neuronal ceroid-lipofuscinoses (NCL): an overview.

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.

Animals↗
PubMed1995

Hematopoietic cell transplantation in fetal lambs with ceroid-lipofuscinosis.

Hematopoietic cells from the liver of normal 45-48-day-old fetal lambs (Hb type AA) were transplanted intraperitoneally into 58-60-day-old recipient fetuses (Hb type BB). The recipient fetuses resulted from mating homozygous ceroid-lipofuscinosis affected males with heterozygous, phenotypically normal, females. The sex of the donor fetus was also recorded. At age 2 1/2 months the recipient lambs with ceroid-lipofuscinosis were diagnosed by histopathology of brain biopsies. Monitoring of blood and bone marrow cells showed that an average of 9% of blood cells in ceroid-lipofuscinosis affected recipients were of donor origin. No differences were evident in the clinical course of disease, brain weight, or histopathology of organs between transplanted and non-transplanted lambs with ceroid-lipofuscinosis. Under the conditions of this experiment, transplantation of fetal hematopoietic cells was not beneficial.

Animals↗