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Biomedical subjects

Junko Matsuda

Publications and source records attributed to Junko Matsuda.

10 recordsLinked to original sources
PubMed2005

Apoptosis accompanied by up-regulation of TNF-alpha death pathway genes in the brain of Niemann-Pick type C disease.

Niemann-Pick disease type C (NP-C) is an autosomal recessive neurovisceral storage disease with neurodegeneration caused by mutations in either the NPC-1 or NPC-2 gene. The murine ortholog of NPC-1 is mutated in BALB/c npc(nih) and this mutant mouse shows equally conspicuous neurodegeneration and loss of neurons. However, the molecular mechanisms causing neurodegeneration in NP-C remain elusive. Here, we report the presence of apoptotic cells detected by both TUNEL staining and electron microscopy in the cerebrum and cerebellum of human patients and the mouse model. Moreover, we found that with progression of the disease process leading to neuronal cell death, an up-regulation of genes involved in the TNF-alpha death pathway caspase-8, FADD, TNFRp55, TRADD, and RIP-by an RNA protection assay. Furthermore, RT-PCR showed that TNF-alpha mRNA expression level also increased up to 30-50-fold in the cerebellum of 7- and 9-week-old NP-C mice compared with wild-type mice. Elevated expression of TNF-alpha was detected in both neurons and astrocytes with TNF-alpha-expressing astrocytes distributed in the affected brain regions. Collectively, our results suggest that the cell death in the brain of NP-C disease occurs through apoptosis and it is mediated by the TNF receptor superfamily pathway.

Animals↗
PubMed2005

Hematopoietic cell transplantation ameliorates clinical phenotype and progression of the CNS pathology in the mouse model of late onset Krabbe disease.

Krabbe disease is a genetic demyelinating disease caused by a deficiency of galactosylceramidase. The majority of cases are of infantile onset with rapid clinical course. A rare late onset form with milder clinical symptoms also exists. The latter form has been reported to respond well to the bone marrow transplantation (BMT) therapy. We tested whether the BMT could be an effective therapy for the mouse model of the late onset form, saposin-A-/- (SAP-A-/-) mice. We used green fluorescent protein transgenic mice as the donors. Chimeric SAP-A-/- mice that received BMT showed very little evidence of neurologic symptoms. At postnatal day 190 when severe demyelination was evident in naive SAP-A-/- mice, demyelination was virtually absent in the brain of chimeric SAP-A-/- mice. Presence of residual enzyme activity, at the time of rapid myelination in SAP-A-/- mice, appears to limit initial inflammatory responses and macrophage infiltration, thereby preventing progression of demyelination in the CNS in SAP-A-/- mice. In contrast, the peripheral nerves showed features of hypertrophic neuropathy with hypomyelination and onion bulb formation, suggesting that there are different cellular responses to the BMT in the CNS and PNS.

Age of Onset↗
PubMed2004

Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in mouse.

The sphingolipid activator proteins (saposins A, B, C and D) are small homologous glycoproteins that are encoded by a single gene in tandem within a large precursor protein (prosaposin) and are required for in vivo degradation of some sphingolipids with relatively short carbohydrate chains. Human patients with prosaposin or specific saposin B or C deficiency are known, and prosaposin- and saposin A-deficient mouse lines have been generated. Experimental evidence suggests that saposin D may be a lysosomal acid ceramidase activator. However, no specific saposin D deficiency state is known in any mammalian species. We have generated a specific saposin D(-/-) mouse by introducing a mutation (C509S) into the saposin D domain of the mouse prosaposin gene. Saposin D(-/-) mice developed progressive polyuria at around 2 months and ataxia at around 4 months. Pathologically, the kidney of saposin D(-/-) mice showed renal tubular degeneration and eventual hydronephrosis. In the nervous system, progressive and selective loss of the cerebellar Purkinje cells in a striped pattern was conspicuous, and almost all Purkinje cells disappeared by 12 months. Biochemically, ceramides, particularly those containing hydroxy fatty acids accumulated in the kidney and the brain, most prominently in the cerebellum. These results not only indicate the role of saposin D in in vivo ceramide metabolism, but also suggest possible cytotoxicity of ceramide underlying the cerebellar Purkinje cell and renal tubular cell degeneration.

Animals↗
PubMed2004

Genetic background markedly influences vulnerability of the hippocampal neuronal organization in the "twitcher" mouse model of globoid cell leukodystrophy.

The twitcher mouse is well known as a naturally occurring authentic mouse model of human globoid cell leukodystrophy (GLD; Krabbe disease) due to genetic deficiency of lysosomal galactosylceramidase. The twitcher mice used most commonly are on the C57BL/6J background. We generated twitcher mice that were on the mixed background of C57BL/6J and 129SvEv, the standard strain for production of targeted mutations. Twitcher mice on the mixed background were smaller and had a shorter lifespan than were those on the C57BL/6J background. Many twitcher mice on the mixed background developed generalized seizures around 30 days that were never seen in twitcher mice on the C57BL/6J background. Neuropathologically, although the degree of the typical demyelination with infiltration of macrophages was similar in the central and peripheral nervous systems, in both strains, marked neuronal cell death was observed only in twitcher mice on the mixed background. In the hippocampus, the neuronal cell death occurred prominently in the CA3 region in contrast to the relatively well-preserved CA1 and CA2 areas. This neuropathology has never been seen in twitcher mice on the C57BL/6J background. Biochemically, the brain of twitcher mice on the mixed background showed much greater accumulation of lactosylceramide. Genetic background must be carefully taken into consideration when phenotype of mutant mice is evaluated, particularly because most targeted mutants are initially on a mixed genetic background and gradually moved to a pure background. These findings also suggest an intriguing possibility of important function of some sphingolipids in the hippocampal neuronal organization and maintenance.

Animals↗
PubMed2004

Comparative clinico-pathological study of saposin-A-deficient (SAP-A-/-) and Twitcher mice.

The Twitcher mouse (twi/twi) has been widely used as an animal model of globoid cell leukodystrophy (GLD; Krabbe disease), a hereditary leukodystrophy due to genetic galactosylceramidase deficiency. Recently, we generated a new mouse model of late-onset, chronic GLD (SAP-A-/- mice) by introducing a mutation (C106F) in the saposin A domain of the sphingolipid activator protein gene. Comparative study of SAP-A-/- and twi/twi mice revealed delay in the onset of neurological symptoms in SAP-A-/- mice (90 days vs 20 to 25 days), milder symptoms, and prolonged average survival (134.4 +/- 29.1 days vs 47.5 +/- 3.9 days). However, in both, the earliest sites of demyelination and macrophage infiltration were in regions of the 8th nerve and the spinal tract of the 5th nerve and spinal-cord, where macrophages could be detected as early as day 30 in asymptomatic SAP-A-/- mice. Furthermore, spacio-temporal pattern of demyelination/macrophage infiltration and the extent of neuropathology at the terminal stage are closely similar in both. These results suggest that peripheral macrophages are readily accessible in these sites and participate in the demyelinating process in the central nervous system.

Age of Onset↗
PubMed2004

Plasma adiponectin levels in newborns are higher than those in adults and positively correlated with birth weight.

OBJECTIVE: The aim of this study was to examine plasma adiponectin concentrations during perinatal the period and their correlations with fetal anthropometric parameters and other hormones. DESIGN: Venous cord blood samples were obtained from 59 full-term healthy newborns (36 males and 23 females, gestational age 37.0-41.4 weeks, birth weight 2,146-4,326 g, birth length 44.0-54.5 cm). The blood samples were also obtained from 15 neonates (postnatal day 3-7) whose cord blood had already been collected and the changes in adiponectin concentrations were examined. MEASUREMENTS: The adiponectin concentration was determined by enzyme-linked immunosorbent assay. The leptin concentration was determined by radioimmunoassay. Insulin, GH and IGF-1 concentrations were determined by immunoradiometric assays. RESULTS: The plasma adiponectin concentrations in cord blood ranged from 6.0 to 55.8 microg/ml (median 22.4 microg/ml), which were much higher than those in normal-weight adults (P < 0.0001). In contrast to the findings in adults, these values were positively correlated with birth weight (r = 0.43, P = 0.0005), body mass index (r = 0.44, P = 0.0005), birth weight/birth length ratio (r = 0.46, P = 0.0002) and the leptin concentrations (r = 0.39, P = 0.004). When the effects of fat mass-related anthropometric parameters such as the birth weight/birth length ratio were controlled, plasma adiponectin concentrations had a significant inverse correlation with insulin concentrations (r = -0.35, P = 0.01). There was no significant gender difference in adiponectin concentrations among newborns. The adiponectin concentrations in neonates (postnatal day 3-7) did not change significantly compared with those in cord blood. CONCLUSIONS: In contrast to the findings in adults, these results suggest that the adiponectin concentration increases with the mass of fetal fat.

Adiponectin↗
PubMed2003

Seminolipid and its precursor/degradative product, galactosylalkylacylglycerol, in the testis of saposin A- and prosaposin-deficient mice.

Sphingolipid activator proteins (saposins A, B, C, and D) are derived from a common precursor protein (prosaposin) and specifically activate in vivo degradation of glycolipids with short carbohydrate chains. A mouse model of prosaposin deficiency (prosaposin-/-) closely mimics the human disease with an elevation of multiple glycolipids. The recently developed saposin A-/- mice showed a chronic form of globoid cell leukodystrophy, establishing the essential in vivo role of saposin A as an activator for galactosylceramidase to degrade galactosylceramide. Seminolipid, the principal glycolipid in spermatozoa, and its precursor/degradative product, galactosylalkylacylglycerol (GalEAG), were analyzed in the testis of the two mouse mutants by electrospray ionization mass spectrometry. Saposin A-/- mice showed the normal seminolipid level, while that of prosaposin-/- mice was approximately 150% of the normal level at the terminal stage. In contrast, GalEAG increased up to 10 times in saposin A-/- mice, whereas it decreased with age in the wild-type as well as in prosaposin-/- mice. These analytical findings on the two saposin mutants may shed some light on the physiological function of seminolipid and GalEAG.

Animals↗
PubMed2003

Ghrelin concentration in cord and neonatal blood: relation to fetal growth and energy balance.

To investigate the relationship between ghrelin and both fetal and neonatal growth parameters and energy balance, we measured plasma ghrelin concentrations in 54 cord blood samples (male, n = 34; female, n = 20; gestational age, 37.0-41.6 wk; birth weight, 2206-4326 g) and 47 neonatal blood samples (male, n = 27; female, n = 20; postnatal d 3-8). The plasma ghrelin concentrations in cord blood ranged from 110.6-446.1 pmol/liter (median, 206.7 pmol/liter), which were equal to or higher than those in normal weight adults. These values were inversely correlated with birth weight (r = -0.40; P = 0.002), birth length (r = -0.36; P = 0.007), placental weight (r = -0.35; P = 0.01), and IGF-I concentration (r = -0.49; P = 0.0002), but were not significantly correlated with the GH concentration (r = 0.22; P = 0.12). The ghrelin concentrations in small for gestational age newborn were significantly higher than those in appropriate for gestational age newborns (P = 0.0008). The ghrelin concentrations in the vein were significantly higher than those in the artery in 8 cord blood samples (P = 0.01), which suggests that the placenta is an important source of fetal ghrelin. In neonates, the ghrelin concentrations ranged from 133.0-481.7 pmol/liter (median, 268.3 pmol/liter), which were significantly higher than those in cord blood (P < 0.0001). These results suggest that ghrelin may contribute to fetal and neonatal growth.

Birth Weight↗
PubMed2002

Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region.

The human pyruvate dehydrogenase complex (PDHC) catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine treatment is very effective for some patients with PDHC deficiency. Among these patients, five mutations of the pyruvate dehydrogenase (E1)alpha subunit have been reported previously: H44R, R88S, G89S, R263G, and V389fs. All five mutations are in a region outside the thiamine pyrophosphate (TPP)-binding region of the E1alpha subunit. We report the biochemical and molecular analysis of two patients with clinically thiamine-responsive lactic acidemia. The PDHC activity was assayed using two different concentrations of TPP. These two patients displayed very low PDHC activity in the presence of a low (1 x 10(-4) mM) TPP concentration, but their PDHC activity significantly increased at a high (0.4 mM) TPP concentration. Therefore, the PDHC deficiency in these two patients was due to a decreased affinity of PDHC for TPP. Treatment of both patients with thiamine resulted in a reduction in the serum lactate concentration and clinical improvement, suggesting that these two patients have a thiamine-responsive PDHC deficiency. The DNA sequence of these two male patients' X-linked E1alpha subunit revealed a point mutation (F205L and L216F) within the TPP-binding region in exon 7.

Binding Sites↗