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S Wurzelmann

Publications and source records attributed to S Wurzelmann.

16 recordsLinked to original sources
PubMed1999

A mouse model for mucopolysaccharidosis type III A (Sanfilippo syndrome).

Mucopolysaccharidosis type III A (MPS III A, Sanfilippo syndrome) is a rare, autosomal recessive, lysosomal storage disease characterized by accumulation of heparan sulfate secondary to defective function of the lysosomal enzyme heparan N- sulfatase (sulfamidase). Here we describe a spontaneous mouse mutant that replicates many of the features found in MPS III A in children. Brain sections revealed neurons with distended lysosomes filled with membranous and floccular materials with some having a classical zebra body morphology. Storage materials were also present in lysosomes of cells of many other tissues, and these often stained positively with periodic-acid Schiff reagent. Affected mice usually died at 7-10 months of age exhibiting a distended bladder and hepatosplenomegaly. Heparan sulfate isolated from urine and brain had nonreducing end glucosamine- N -sulfate residues that were digested with recombinant human sulfamidase. Enzyme assays of liver and brain extracts revealed a dramatic reduction in sulfamidase activity. Other lysosomal hydrolases that degrade heparan sulfate or other glycans and glycosaminoglycans were either normal, or were somewhat increased in specific activity. The MPS III A mouse provides an excellent model for evaluating pathogenic mechanisms of disease and for testing treatment strategies, including enzyme or cell replacement and gene therapy.

Animals↗
PubMed1996

Metabolic abnormalities in feline Niemann-Pick type C heterozygotes.

Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lysosomal storage disorder in which cholesterol lipidosis results from defective intracellular transport of unesterified cholesterol. The primary molecular defect of NPC is unknown; regulatory mechanisms of cholesterol metabolism are impaired, resulting in retarded esterification of exogenous cholesterol with accumulation of unesterified cholesterol in lysosomes and secondary storage of glycolipids and sphingomyelin. In obligate heterozygotes from a feline NPC model, cultured skin fibroblasts challenged with exogenously derived cholesterol exhibited intermediate rates of cholesterol esterification and accumulation of unesterified cholesterol. Liver lipid analyses of obligate heterozygote cats demonstrated intermediate cholesterol and sphingomyelin concentrations. Vacuolated skin fibroblasts were found in 2 of 3 heterozygote cats, and occasional cortical neurons exhibited intracellular inclusions immunoreactive for GM2-ganglioside. Ultrastructural studies provided evidence of storage in liver and brain. We believe these morphological and biochemical findings are the first example of manifestations of CNS abnormalities in a genetic carrier for a neuronal storage disease.

Animals↗
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

Morphological alterations in neocortical and cerebellar GABAergic neurons in a canine model of juvenile Batten disease.

The pathogenesis of brain dysfunction in a canine model of juvenile Batten disease was studied with techniques designed to determine sequential changes in mitochondrial morphology and cytochrome oxidase (CO) activity, and in neurons and synapses using gamma-aminobutyric acid (GABA) as a neurotransmitter. Histochemical and immunocytochemical methods were employed. Mitochondrial alterations were found in a select population of nonpyramidal neurons in neocortex and claustrum, and in cerebellar basket cells. Proportions of affected neurons at any one time remained constant over the disease course, with morphologically-abnormal mitochondria first being recognized at age 6 months. Enlarged mitochondria were readily identifiable at the light microscope (LM) level as large CO-positive or mitochondrial antibody-positive granular structures. Colabelling with antibodies to GABA or to parvalbumin (PV) indicated that most of these cells were GABAergic. Ultrastructurally, atypical mitochondria were characterized by globular enlargement, intramitochondrial membranous inclusions, and disorganized internal structure. CO activity in all other cell somata and in neuropil was diminished compared with normal, age-matched tissue. Glutamic acid decarboxylase (GAD), PV, and GABA studies demonstrated loss of GABAergic neurons and synapses in cortex and cerebellum of affected dogs. These results indicate that abnormal mitochondria are present in neurons in Batten disease, and suggest that suboptimal mitochondrial function may play a role in the pathogenic mechanisms of brain dysfunction in this disorder.

Animals↗
PubMed1994

Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease.

Neuronal storage disorders are fatal neurodegenerative diseases of humans and animals that are caused by inherited deficiencies of lysosomal hydrolase activity. Affected individuals often appear normal at birth but eventually develop progressive neurologic symptoms including sensory and motor deficits, mental retardation, and seizures. We have examined efficacy of bone marrow transplantation as a means of enzyme replacement, using cats with the lysosomal storage disease alpha-mannosidosis. Treated animals showed little or no progression of neurologic signs 1-2 years after transplant, whereas untreated cats became severely impaired and reached endstage disease by 6 months of age. Increased lysosomal alpha-mannosidase activity was found in brain tissue of the treated animals, and electron microscopy revealed no evidence of lysosomal storage within most neurons. Histochemical localization of acidic alpha-D-mannoside mannohydrolase (EC 3.2. 1.24), using 5-bromo-4-chloro-3-indolyl alpha-D-mannopyranoside, showed that functional enzyme was present in neurons, glial cells, and cells associated with blood vessels. This study provides direct evidence that bone marrow transplantation as treatment for a neuronal storage disease can lead to significant levels of a missing lysosomal hydrolase within neurons of the central nervous system and to compensation for the genetic metabolic defect.

Animals↗
PubMed1990

Distribution of ectopic neurite growth and other geometrical distortions of CNS neurons in feline GM2 gangliosidosis.

Golgi and combined Golgi-electron microscopic (EM) studies were carried out on cats in the terminal stages of GM2 ganglioside storage disease and the resulting data were compared with those from similar studies of other neuronal storage diseases in cats, including GM1 gangliosidosis. The results support the view that only limited types of neurons affected by the lysosomal hydrolase deficiency and subsequent intracellular storage have the capacity to sprout new dendritic-like growth processes from their axon hillocks, and that these neurons are essentially the same in all of these diseases studied to date. Golgi studies of CNS tissues from GM2 gangliosidosis cats revealed ectopic neurite growth on pyramidal neurons of cerebral cortex and multipolar cells of amygdala and claustrum, whereas other types of neurons responded to the metabolic defect with aspiny meganeurite formation or somatic enlargement, or appeared normal in terms of soma-dendritic morphology. Combined Golgi-EM studies of cortical pyramidal neurons revealed that ectopic, axon hillock neurites commonly possessed asymmetrical synapses which were similar to those observed in other storage disorders.

Animals↗
PubMed1988

Ectopic dendritogenesis and associated synapse formation in swainsonine-induced neuronal storage disease.

Ectopic dendrite growth and new synapse formation are known to occur on select kinds of neurons in a wide variety of neuronal storage diseases. As these changes in connectivity occur just proximal to the axonal initial segment, it has been hypothesized that they underlie the generation of abnormal neuronal function in these diseases. We have studied certain aspects of this phenomenon through the use of a plant-derived indolizadine alkaloid, swainsonine, which specifically inhibits the lysosomal hydrolase, alpha-mannosidase. These studies fully document the close morphological similarity between swainsonine-induced and inherited feline alpha-mannosidosis. This includes the presence of clear and floccule-filled storage vacuoles, as seen with routine EM, and axon hillock neurite growth on select cell types, as seen with Golgi staining. The latter was found only on cortical pyramidal neurons and multipolar cells of amygdala, and these same cell types are known to be involved in ectopic neuritogenesis in other storage diseases. Combined Golgi-electron-microscopic studies demonstrated the presence of normal-appearing synapses on these aberrant neuritic processes and also unusual, membranous inclusions specifically within the neurite-bearing pyramidal cells. The latter may be indicative of unique metabolic changes in these neurons and is consistent with the hypothesis that storage of gangliosides or other glycolipids underlies the recapitulation of dendritic growth features in these diseases. Experimental manipulation of the disease process using the swainsonine model indicated that induction of cortical pyramidal neuron neurite growth could be influenced by both age of onset and intensity of intraneuronal storage. Although Golgi studies clearly demonstrated neuritic sprouting in animals with disease onset as late as at 1 year, cortical pyramidal cells of older, adult animals appeared to undergo significant storage without a similar induction of neurite growth. These studies support the view that induced neuritogenesis in neuronal storage disease is associated with changes in metabolism, specifically within the neurite-bearing cells, that this change possibly involves gangliosides, and that the neuritogenic response may be limited to pre-adult stages of brain maturation.

Alkaloids↗
PubMed1987

Ectopic axon hillock-associated neurite growth is maintained in metabolically reversed swainsonine-induced neuronal storage disease.

An experimentally induced and reversible model of a neuronal storage disease, swainsonine-induced feline alpha-mannosidosis, has been used to study the modifiability of ectopic, axon hillock-associated neurites and their new synaptic contacts. Earlier studies have fully documented that a variety of neuronal storage disorders are characterized by such changes in neuronal geometry and connectivity. Swainsonine administration was ended after 6 months of continuous treatment which had resulted in characteristic signs of alpha-mannosidosis. Studies of this animal 6 months after reversal showed that even though neuronal vacuolation and other CNS changes essentially normalized, ectopic neurites and their synaptic connections were still present and appeared similar to those of another animal which had been treated with swainsonine for the entire 12-month period. These results suggest that once initiated during the disease process, ectopic axon hillock-associated dendrites become an integral part of the soma-dendritic domain of affected neurons and may not be reversible. These findings may have relevance for current attempts to devise therapies involving enzyme replacement for individuals with inherited neuronal storage disease.

Alkaloids↗
PubMed1982

Microtubule disarray in cortical dendrites and neurobehavioral failure. I. Golgi and electron microscopic studies.

Cortical biopsies obtained from 5 young children with severe neurobehavioral retardation of unknown etiology have been analyzed using Golgi and EM techniques. The normally cylindrical geometry of individual dendritic processes of pyramidal and non-pyramidal neurons is interrupted by the formation of distinct varicosities. While over 90% of observed cells are affected, the extent of varicosity formation varies from cell to cell and is most prominent in medium and small pyramidal cells. Varicosities may occur in the periphery only, or they may extend proximally to primary dendritic trunks. Accompanying changes include thin and irregular proximal processes, loss of dendritic spines, and predominance of long, thin tortuous spines. Ultrastructural analysis reveals characteristic changes in the cytoskeleton of these processes. Microtubules, within the larger proximal processes, twist and turn, relative to one another and relative to the long axis of the process. In varicose regions, microtubules course in roughly parallel array through constricted segments, only to splay away from one another on entering an expansion. Synapses are evident on constricted and expanded segments, as well as on spines. Alterations in dendritic structure of both pyramidal and non-pyramidal neurons may represent a primary target in the pathobiological process underlying neurobehavioral failure.

Cerebral Cortex↗
PubMed1981

Ultrastructure of neurites and meganeurites of cortical pyramidal neurons in feline gangliosidosis as revealed by the combined Golgi-EM technique.

Application of the Golgi-EM technique to the study of altered cortical pyramidal neuron morphology in feline gangliosidosis has revealed the presence of aberrant synapses in relation to multiple neurites and secondary neurites of meganeurites. In addition fine neurites arising from the soma and meganeurite are found to project into and envelope elements of the surrounding neuropil. These observations provide further evidence for a disturbance in neuronal surface membrane regulation in ganglioside storage disease.

Animals↗
PubMed1978

Neurosecretion. XVII. Experimentally induced release of neurosecretory material by exocytosis in the insect Leucophaea maderae.

In the corpora cardiaca of the insect Leucophaea the administration of serotonin elicits ultrastructural features indicative of the extrusion of neurosecretory material by exocytosis. The response to the stimulus and the process of extrusion seem to occur at considerable speed. Nearly all of the 30 test animals, fixed at various intervals starting as early as 3 min after the injection of the drug, show granules captured at the moment of leaving the axon as well as fully exteriorized secretory material. The fact that many of these granules are much smaller than the typical neurosecretory type speaks for intracellular fragmentation of the latter prior to the discharge of this cellular product. After 25 min or more the extruded electron dense structures show signs of breakdown. 3the apparent speed of these phenomena accounts for the dearth of omega-type configurations observed in unstimulated specimens of this species. The possible relationship between the membrane phenomena involved in exocytosis and the transient protrusions of bounding membranes of neurosecretory granules described in earlier papers remains to be clarified.

Animals↗
PubMed1977

Neurosecretion. XVI. Protrusions of bounding membranes of neurosecretory granules.

Protrusions of bounding membranes of neurosecretory granules, comparable to those demonstrated by Castel (1977) in the mammalian neurohypophysis, were observed under various experimental conditions in the corpora cardiaca of the insects Leucophaea maderae and Periplaneta americana. Electrical stimulation in vitro of the nervus corporis cardiaci I, which elicited a marked rise in the amount of neurohormone discharged, as determined by bioassay, also yielded a significantly larger number of membrane protrusions than were observed in unstimulated controls. However, no comparable response was obtained in glands subjected to stimulation of hormone release by exposure to serotonin or high potassium concentrations. On the other hand, membrane protrusions were numerous under certain conditions not expected to stimulate neurohormone release, i.e., in tissue exposed to a zinc iodide mixture without prior fixation. The present results support the conclusion drawn by Castel that these configurations appear to be related to the process by which neurosecretory material is discharged. Too transient to be much in evidence under physiological condition, they become more prominent not only after appropriate acceleration of the rate of release, but also when such membrane arrangements are "frozen" by procedures that interfere with the regular milieu.

Animals↗