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H J Baker

Publications and source records attributed to H J Baker.

At least 37 records · Page 2Linked to original sources
PubMed1990

Initiation and growth of ectopic neurites and meganeurites during postnatal cortical development in ganglioside storage disease.

The incidence of cortical pyramidal neurons displaying meganeurites or enlarged axon hillocks with ectopic spines and neurites was evaluated developmentally using feline models of GM1 and GM2 gangliosidosis. Results of these studies demonstrated that the onset of ectopic neurite growth occurred after the elaboration of dendrites on cortical pyramidal neurons, and that the time of onset of this renewed dendritogenesis was similar in the two diseases. Initiation and growth of ectopic neurites also correlated in a general way with onset and progression of clinical deterioration in both diseases. In GM1 gangliosidosis there was a greater tendency toward formation of meganeurites, whereas in cats with GM2 gangliosidosis the growth of ectopic axon hillock neurites without meganeurites predominated. At end-stage disease in GM2 gangliosidosis, nearly 90% of pyramidal cells displayed some degree of axon hillock neurite growth as opposed to less than half this number for GM1 gangliosidosis cats at the same age. These data are consistent with the hypothesis that there are two separate driving forces behind these somadendritic abnormalities of pyramidal neurons in the gangliosidoses. Excessive intraneuronal accumulation of storage vacuoles accounts for the formation of meganeurites, whereas some type of intrinsic metabolic defect results in axon hillock neurite growth which in turn offers new surface area for synaptic input. Currently available data indicate that GM2 or GM3 ganglioside, or a closely related metabolic product other than GM1 ganglioside, may be primarily associated with the growth of ectopic dendritic processes on morphologically mature neurons in storage diseases.

Animals↗
PubMed1988

Diagnosis of feline GM1 gangliosidosis by enzyme assay of cultured conjunctival cells.

GM1 gangliosidosis is characterized by a deficiency in the lysosomal hydrolase beta-galactosidase, progressive nervous system disease and ocular lesions. Diagnosis of GM1 gangliosidosis in humans and cats with the analogous disease has been made by measurement of the enzyme activity in various tissues including brain, liver and cultured skin fibroblasts. The authors report the use of cultured conjunctival cells for this purpose derived from cats with feline GM1 gangliosidosis, a model of the human disease (juvenile GM1 gangliosidosis, Derry's disease). Full thickness conjunctival biopsies from three cats with GM1 gangliosidosis and two normal controls were used to initiate cell cultures. Optimal conditions for beta-galactosidase activity were established with an uncultured conjunctival biopsy from a normal cat. The fluorgen, 4-methylumbelliferyl-beta-D-galactopyranoside was used as substrate. After 2 months in culture, and 2 weeks after subculture, cells from cats affected with GM1 gangliosidosis exhibited specific activities for beta-galactosidase of 10, 9 and 12 nmoles 4MU/hr/mg protein, whereas specific activities for normals were 630 and 469 nmoles 4MU/hr/mg. Enzymatic analysis of cultured conjunctival cells may offer an effective alternative for the diagnosis of GM1 gangliosidosis.

Animals↗
PubMed1987

Reduced Ca2+ flux in synaptosomes from cats with GM1 gangliosidosis.

Ca2+ transport was studied in synaptosomes prepared from normal cats and cats with GM1 gangliosidosis. The influx of Ca2+ was found to be a biphasic process in synaptosomes from both GM1 mutant and normal cats. Both the fast and slow phases of voltage-dependent Ca2+ uptake were significantly reduced in cats with the lysosomal storage disease, however the inhibitory mechanisms differed. The fast phase of Ca2+ uptake was inhibited uncompetitively, whereas the slow phase was inhibited competitively. In addition, Na+-dependent Ca2+ efflux was reduced significantly in cats with GM1 gangliosidosis. Since it is well established that maintenance of Ca2+ homeostasis is essential for normal neuronal function, a ganglioside-induced disruption of Ca2+ transport across synaptic membranes may be responsible, in part, for the neuronal dysfunction characteristic of GM1 gangliosidosis.

Animals↗
PubMed1987

Animal model: ceroidosis (ceroid-lipofuscinosis) in Australian cattle dogs.

Ceroid-lipofuscinosis is described in Australian Cattle dogs. Lesions included storage of ceroid-lipofuscin in most tissues with characteristic ultrastructural inclusion body patterns in neurons and other cells. Dolichol concentration of the affected dog's brain was similar to those in age-matched control dog brains. However, concentrations in brain, liver and kidneys were markedly higher than in a slightly younger dog. Biochemical data including lysosomal enzyme activities exclude other lysosomal storage diseases. The clinical and pathological features of this disorder resemble those of the juvenile Spielmeyer-Vogt type of Batten disease in humans.

Age Factors↗
PubMed1987

Sphingomyelin lipidosis in a cat.

A 7-month-old Balinese cat with progressive neurological dysfunction had histopathological lesions of brain, liver, kidney, spleen, and lung consistent with a lysosomal storage disease. Ultrastructural examination revealed lysosomal hypertrophy with membranous inclusions. Hepatic sphingomyelin and cholesterol were elevated 10 times normal, and total phospholipids were increased 3.6 fold. Sphingomyelinase activity measured with 14C labeled sphingomyelin at pH 5.0 was virtually absent in brain and liver. Other lysosomal hydrolase activities were normal or elevated. Clinical, morphological, and biochemical findings suggest that this cat had sphingomyelin lipidosis similar to human Niemann-Pick disease type A, and that feline sphingomyelin lipidosis provides another model of human lysosomal storage disease.

Animals↗
PubMed1986

Increased acetylcholine synthesis and release in brains of cats with GM1 gangliosidosis.

Cholinergic processes were measured in motor cortex, hippocampus, and striatum of cats in the terminal stages of GM1 gangliosidosis and compared to those of control cats. The greatest difference observed was elevation in the rate of K+-stimulated release of acetylcholine (ACh) from brain slices prepared from affected cats. The K+-stimulated release of endogenous ACh was increased by 31-43% and of newly synthesized ACh by 19-80% in brain slices from different brain regions. All regions that were examined were affected but the greatest effects occurred in cortex. The rate of synthesis of ACh was elevated in cortical and hippocampal slices. Choline acetyltransferase activity in brain regions of cats with GM1 gangliosidosis was not significantly different from that in controls, whereas high-affinity choline transport in cortical synaptosomes was elevated. Muscarinic receptor binding sites were reduced in the cortex, hippocampus, and striatum of GM1 mutant cats, whereas the apparent affinity was not altered. These results indicate that there are major alterations of cholinergic function in the brains of cats with GM1 gangliosidosis.

Acetylcholine↗
PubMed1985

Increased metabolism of acetylcholine in brain of cats with Gm1 gangliosidosis.

Acetylcholine metabolism was studied in cats with Gm1 gangliosidosis. Marked increases in acetylcholine synthesis (130% of controls) and K+-stimulated release of ACh (142-165% of controls) were observed in cortical and hippocampal brain slices of diseased cats. Cortical synaptosomes prepared from affected cats had significantly elevated rates of high affinity choline transport (131% of controls). These results indicate that in Gm1 gangliosidosis there is an unique disease-induced activation of cholinergic activity in the nervous system. These changes may result from disease-induced proliferation of functional cholinergic nerve endings and/or altered regulation of acetylcholine metabolism.

Acetylcholine↗
PubMed1985

Fluorescence polarization analysis, lipid composition, and Na+, K+-ATPase kinetics of synaptosomal membranes in feline GM1 and GM2 gangliosidosis.

Neurochemical studies were performed on synaptosomal membranes from cats with GM1 or GM2 gangliosidosis to examine possible mechanisms of neuronal dysfunction in these disorders. The basic hypothesis tested was that deficient ganglioside catabolism causes increased ganglioside content of synaptosomal plasma membrane which in turn disrupts normal function. Fluidity characteristics of synaptosomal membranes were examined using fluorescence polarization. Results showed markedly reduced membrane fluidity in both GM1 and GM2 gangliosidosis. These results were supported by a second study which revealed that isolated synaptosomal membranes of GM1 gangliosidosis cats had a 24-fold increase in total ganglioside content caused predominantly by excess GM1, a 2.3-fold increased cholesterol content, and a 1.4-fold increased phospholipid content. Finally, kinetic analysis of synaptosomal plasma membrane Na+,K+-ATPase from cats with GM1 gangliosidosis showed negligible differences in kinetic parameters compared with controls. Thus, the enzyme appeared protected from the global membrane changes in fluidity and composition. These observations provide evidence for a pathogenetic mechanism of neuronal dysfunction in the gangliosidoses while demonstrating protection of certain vital functional components, such as Na+,K+-ATPase.

Animals↗
PubMed1984

Sphingomyelin lipidosis in a cat: Golgi studies.

Alterations in neuronal geometry in a feline model of sphingomyelin lipidosis were evaluated using Golgi staining. Neurons in cerebral cortex, basal ganglia, amygdala, thalamus, and cerebellum were impregnated and many were found to possess conspicuous enlargements at the axon hillock-initial segment region (meganeurites) and/or to sprout secondary neuritic processes from this same area. The latter were sometimes well developed and resembled small dendrites. These changes were cell type specific with distribution limited to certain types of neurons in select brain regions, while others remained normal, or underwent only simple somatic enlargement or generalized degenerative changes. Occasional cortical pyramidal neurons also displayed thinning of dendrites and extensive loss of dendritic spines. These observations add sphingomyelin lipidosis to other neuronal storage disorders in which aberrant neurite growth and meganeurite formation accompany lysosomal enzyme deficiency and the associated metabolic alterations and storage. Although meganeurite-like expansions have been reported to occur in many storage disorders, the appearance of axon hillock-associated neurite growth on morphologically mature neurons has been identified heretofore only in the gangliosidoses, and in feline models of alpha-mannosidosis and mucopolysaccharidosis type 1.

Amygdala↗
PubMed1984

Characterization of the rat mutant dystonic (dt): a new animal model of dystonia musculorum deformans.

An inherited neurological disorder characterized by sustained twisting movements during waking has been discovered in Sprague-Dawley rats. The mutation follows an autosomal recessive pattern of inheritance and has been named dystonic (dt). The rat mutants are indistinguishable from normal littermates in open field behavior and climbing activity prior to postnatal days 9 to 10. Clinical signs begin to appear on day 10 and include twisting of the axial musculature, hyperflexion of the trunk, self-clasping of forelimbs and hindlimbs, and poor placement of the limbs during locomotion. No morphological lesions of neural or non-neural tissues have been observed with routine light microscopy. Dystonic rats demonstrate significantly elevated cerebellar norepinephrine levels, although levels in other terminal fields of the locus ceruleus are similar to those of normal littermates. No differences in the pattern or density of noradrenergic innervation were apparent in cerebellar tissue from dt rats examined with histochemical fluorescence techniques. These mutants were less sensitive than unaffected littermates to the akinesic effects of the dopamine blocker haloperidol. However, striatal dopamine levels were not reliably different from normal in dt rats, and their response to the movement-stimulating effects of apomorphine appeared normal. These findings suggest the presence of biochemical disturbances in the extrapyramidal system of dt rats. The dt rat may provide a useful model for human dystonia musculorum deformans.

Aging↗
PubMed1982

Neurotransmitter chemistry in feline GM1 gangliosidosis: a model for human ganglioside storage disease.

Assays for synaptosomal high-affinity uptake activity (glutamate, gamma-aminobutyric acid, norepinephrine), neurotransmitter synthesizing enzymes (choline acetyltransferase, glutamate decarboxylase, tyrosine hydroxylase), and endogenous neurotransmitters were performed in cats with advanced inherited GM1 gangliosidosis. A significant reduction in uptake activity, ranging from 24 to 77% of control, was demonstrated in motor, occipital, and cerebellar brain regions. This reduction was unassociated with comparable alterations in neurotransmitter levels or synthesizing enzyme activity. We hypothesize that the defect of neurotransmitter inactivation is part of an overall abnormality of synaptic membrane function that could contribute to the neurological symptoms seen in the hereditary gangliosidoses.

Animals↗