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Biomedical subjects

Nobuyuki Takei

Publications and source records attributed to Nobuyuki Takei.

At least 19 recordsLinked to original sources
PubMed2026

Replication analysis of the PRKN V380L (rs1801582) variant in a Japanese cohort of spinocerebellar ataxia type 3.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is caused by CAG repeat expansion in ATXN3, which inversely correlates with age at onset but does not fully account for interindividual variability. A recent study in a mixed European/South and North&#xa0;American cohort suggested that the PRKN V380L variant (rs1801582), particularly in C/C homozygotes, was associated with earlier disease onset. We therefore performed a replication analysis to evaluate the frequency and potential clinical relevance of rs1801582 in a Japanese SCA3 cohort. METHODS: rs1801582 genotypes were determined by Sanger sequencing in 228 genetically confirmed SCA3 patients and 260 SCA6 patients as convenience disease controls. Genotype frequencies were additionally compared with East Asian reference populations from the 1000 Genomes Project Phase 3 dataset. Associations with age at onset were evaluated using multivariable linear regression adjusted for expanded ATXN3 CAG repeat length, normal ATXN3 CAG repeat length, and sex. RESULTS: Genotype frequencies in SCA3 (G/G: 86.0%, G/C: 13.2%, C/C: 0.9%) were similar to those in controls (G/G: 85.8%, G/C: 13.5%, C/C: 0.8%) and closely resembled those reported in East Asian reference populations. Because of the extremely small number of C/C carriers (n&#x2009;=&#x2009;2), subsequent analyses focused on G/G and G/C carriers. In SCA3, median age at onset was comparable between genotypes (42 vs. 41&#xa0;years), and median expanded ATXN3 CAG repeat lengths did not differ between groups (71 vs. 71 repeats). Multivariable regression analysis adjusting for expanded ATXN3 CAG repeat length, normal ATXN3 CAG repeat length, and sex demonstrated that rs1801582 was not independently associated with age at onset (&#x3b2;&#x2009;= -&#x2009;0.42&#xa0;years, p&#x2009;=&#x2009;0.84), whereas expanded CAG repeat length remained a strong predictor (&#x3b2;&#x2009;= -&#x2009;1.68&#xa0;years per repeat, p&#x2009;<&#x2009;0.0001). CONCLUSIONS: The rs1801582 C/C genotype is extremely rare in Japan; therefore, the present cohort had limited statistical power to directly evaluate the previously proposed recessive modifier effect. No detectable association between rs1801582 genotype and age at onset was identified among G/G and G/C carriers in this Japanese cohort. These findings highlight the importance of population-specific validation and adequately powered replication studies when evaluating candidate genetic modifiers in SCA3.

Adult↗
PubMed2006

Neonatal exposure to epidermal growth factor induces dopamine D2-like receptor supersensitivity in adult sensorimotor gating.

RATIONALE: Abnormality in the neurotrophic factor for dopamine neurons, epidermal growth factor (EGF), is associated with schizophrenia. Thus, rats treated with EGF as neonates are used as a putative animal model for schizophrenia showing impaired prepulse inhibition (PPI) and other cognitive deficits in the adult stage. OBJECTIVES: To elucidate the abnormal behavioral traits of this animal model, the EGF effects on the dopaminergic system were analyzed pharmacologically and biochemically at the adult stage. RESULTS: We examined the effects of subthreshold doses of dopamine agonists on PPI in this model. A non-selective dopamine agonist, apomorphine (0.1 mg/kg), decreased PPI in EGF-treated rats, but not in controls. Further, a D(2)-like receptor agonist, quinpirole (0.01 and 0.03 mg/kg), similarly decreased PPI in EGF-treated rats but had no effect in the control animals. In contrast, a D(1)-like receptor agonist, SKF38393 (3 and 10 mg/kg), had no effect on PPI in both groups. To explore the molecular mechanism underlying the change in sensorimotor gating, we assessed D(1) and D(2) receptors expression in the prefrontal cortex, striatum and hippocampus and their downstream signaling. Although there were no significant differences in basal receptor levels, quinpirole administration significantly enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) in the striatum of EGF-treated rats. CONCLUSION: These results suggest that circulating EGF in the early development substantially influences D(2) receptor-dependent regulation of sensorimotor gating.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2006

Possible involvement of BDNF release in long-lasting synapse formation induced by repetitive PKA activation.

For the analysis of the cellular mechanism underlying long-term synaptic plasticity, a model system that allows long-lasting pursuit is required. Previously we reported that, in hippocampal neurons under dissociated cell culture conditions, repeated (but not a single) transient activation of protein kinase A (PKA) led to an increase in the number of synapses that lasted >3 weeks, and hence we proposed that this phenomenon should serve as an appropriate model system. Here we report that repeated pulsatile application of brain-derived neurotrophic factor (BDNF) leads to persistent synapse formation equivalent to that after the repeated transient activation of PKA. A BDNF-scavenging substance applied concomitantly with PKA activation abolished the synapse formation. The release of BDNF upon PKA activation was confirmed by phosphorylation of TrkB. These results indicate that the release of BDNF is involved in the putative signaling cascade connecting PKA activation and synapse formation.

Animals↗
PubMed2006

Activity-dependent shedding of heparin-binding EGF-like growth factor in brain neurons.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is initially produced as a membrane-anchored precursor (pro-HB-EGF) and subsequently liberated from the cell membrane through ectodomain shedding. Here, we characterized the molecular regulation of pro-HB-EGF shedding in the central nervous system. Cultured neocortical or hippocampal neurons were transfected with the alkaline-phosphatase-tagged pro-HB-EGF gene and stimulated with various neurotransmitters. Both kainate and N-methyl-D-aspartate, but not agonists for metabotropic glutamate receptors, promoted pro-HB-EGF shedding and HB-EGF release, which were attenuated by an exocytosis blocker and metalloproteinase inhibitors. In the brain of transgenic mice over-expressing human pro-HB-EGF, kainate-induced seizure activity decreased content of pro-HB-EGF-like immunoreactivity and conversely increased levels of soluble HB-EGF. There was concomitant phosphorylation of EGF receptors (ErbB1) following seizures, suggesting that seizure activities liberated HB-EGF and activated neighboring ErbB1 receptors. Therefore, we propose that glutamatergic neurotransmission in the central nervous system plays a crucial role in regulating ectodomain shedding of pro-HB-EGF.

Animals↗
PubMed2006

Demonstration of quantum telecloning of optical coherent states.

We demonstrate unconditional telecloning for the first time. In particular, we symmetrically and unconditionally teleclone coherent states of light from one sender to two receivers, achieving a fidelity for each clone of F = 0.58 +/- 0.01, which surpasses the classical limit. This is a manipulation of a new type of multipartite entanglement whose nature is neither purely bipartite nor purely tripartite.

Journal Article↗
PubMed2006

Transforming growth factor alpha attenuates the functional expression of AMPA receptors in cortical GABAergic neurons.

In the developing neocortex, brain-derived neurotrophic factor (BDNF) exerts a trophic activity to increase the expression and channel activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor subunits. Here, we demonstrate that the epidermal growth factor (EGF) receptor (ErbB1) ligands exert the opposite biological activity in cultured neocortical neurons. Subchronic stimulation of ErbB1 with transforming growth factor alpha (TGFalpha), EGF, or heparin-binding EGF (HB-EGF) down-regulated protein expression of the GluR1 AMPA receptor subunit in cultured neocortical neurons. In agreement, TGFalpha treatment decreased the Bmax of [3H] AMPA binding and GluR1 mRNA levels. Immunocytochemistry revealed that the decrease in GluR1 was most pronounced in multipolar GABAergic neurons. To examine the physiological consequences, we recorded AMPA-evoked currents as well as miniature excitatory postsynaptic currents in morphologically identified putative GABAergic neurons in culture. Subchronic TGFalpha treatment decreased AMPA-triggered currents as well as the amplitude and frequency of miniature excitatory postsynaptic currents. An ErbB1 tyrosine kinase inhibitor, PD153035, inhibited the TGFalpha effect. Moreover, TGFalpha counteracted the neurotrophic activity of BDNF on AMPA receptor expression. Co-application of TGFalpha with BDNF blocked the BDNF-triggered up-regulation of AMPA receptor expression and currents. These observations reveal a negative regulatory activity of the ErbB1 ligand, TGFalpha, which reduces the input sensitivity of cortical GABAergic neurons to attenuate their inhibitory function.

Animals↗
PubMed2005

Differential distributions of peptides in the epidermal growth factor family and phosphorylation of ErbB 1 receptor in adult rat brain.

Using two-site enzyme immunoassays, we measured protein levels of epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), and heparin-binding epidermal growth factor (HB-EGF) in adult rat brain, and compared them with the phosphorylation levels of their receptor (ErbB 1). There were significant variations in the brain distributions of each ErbB 1 ligand. Among these ErbB 1 ligands, HB-EGF protein levels were higher than those of TGF alpha and those of EGF were the lowest. TGF alpha protein was relatively enriched in the midbrain regions, while HB-EGF levels were most abundant in the cerebellum. Protein distributions of the EGF family members were discordant with previously reported mRNA distributions. In addition, there was significant basal ErbB 1 phosphorylation detected with the largest amount of activation in the midbrain. These observations suggest that the activation of brain ErbB 1 involves post-translational regulation of multiple EGF family members in a region-specific manner.

Animals↗
PubMed2005

Enhancement of translation elongation in neurons by brain-derived neurotrophic factor: implications for mammalian target of rapamycin signaling.

The effects and signaling mechanisms of brain-derived neurotrophic factor (BDNF) on translation elongation were investigated in cortical neurons. BDNF increased the elongation rate approximately twofold, as determined by measuring the ribosomal transit time. BDNF-accelerated elongation was inhibited by rapamycin, implicating the mammalian target of rapamycin (mTOR). To explore the mechanisms underlying these effects, we examined the protein phosphorylation cascades that lead to the activation of translation elongation in neurons. BDNF increased eukaryote elongation factor 1A (eEF1A) phosphorylation and decreased eEF2 phosphorylation. Whereas eEF2 phosphorylation levels altered by BDNF were inhibited by rapamycin, eEF1A phosphorylation was not affected by rapamycin or PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor. BDNF induced phosphorylation of eEF2 kinase (Ser366), as well as decreased its kinase activity. All these events were inhibited by rapamycin. Furthermore, mTOR siRNA, which reduced mTOR levels up to 50%, inhibited the BDNF-induced enhancement in elongation rate and decrease in eEF2 phosphorylation. These results strongly suggest that BDNF enhances translation elongation through the activation of the mTOR-eEF2 pathway.

Animals↗
PubMed2005

High-fidelity teleportation beyond the no-cloning limit and entanglement swapping for continuous variables.

We experimentally demonstrate continuous-variable quantum teleportation beyond the no-cloning limit. We teleport a coherent state and achieve the fidelity of 0.70 +/- 0.02 that surpasses the no-cloning limit of 2/3. Surpassing the limit is necessary to transfer the nonclassicality of an input quantum state. By using our high-fidelity teleporter, we demonstrate entanglement swapping, namely, teleportation of quantum entanglement, as an example of transfer of nonclassicality.

Journal Article↗
PubMed2005

Distinct influences of neonatal epidermal growth factor challenge on adult neurobehavioral traits in four mouse strains.

Epidermal growth factor (EGF) receptor (ErbB1) signals regulate dopaminergic development and function and are implicated in schizophrenia. We evaluated genetic effects on neurobehavioral changes induced by neonatal EGF administration, using four mouse strains. Subcutaneous EGF administration increased phosphorylation of brain ErbB1 in all strains, although DBA/2 and C57BL/6 mice had lower basal phosphorylation. Neonatal EGF treatment differentially influenced physical and behavioral/cognitive development, depending on mouse strain. Prepulse inhibition was decreased in DBA/2 and C57BL/6 mice but not C3H/He and ddY mice. Locomotor activity was accelerated in DBA/2 mice, but reduced in ddY mice. EGF treatment enhanced fear-learning performance with a tone cue in DBA/2 mice, but decreased performance with tone and context cues in C3H/He and ddY mice, respectively. The strain-dependent behavioral sensitivity was correlated with basal ErbB1 phosphorylation. Genetic components regulating brain ErbB1 signaling strongly influence the direction and strength of behavioral responses stemming from the neonatal neurotrophic perturbation.

Acoustic Stimulation↗
PubMed2005

Müller Cells as a source of brain-derived neurotrophic factor in the retina: noradrenaline upregulates brain-derived neurotrophic factor levels in cultured rat Müller cells.

Müller cells, the predominant glial cells in the retina, are thought to play important roles in the survival of retinal neurons. Previous studies have demonstrated that Müller cells express brain-derived neurotrophic factor (BDNF), which has a pronounced neurotrophic effect on retinal ganglion cells. In this study, we investigated whether Müller cells express and release BDNF in culture. Reverse transcriptase-PCR, immunocytochemistry and Western blotting revealed that Müller cells produce BDNF mRNA and protein. Using the enzyme-linked immunosorbant assay, BDNF protein levels in Müller cells and their conditioned medium were quantified, demonstrating that Müller cells produce and release high levels of BDNF. Noradrenaline administration caused an upregulation of BDNF mRNA and protein expression by cultured Müller cells. These results suggest that Müller cells may act as an endogenous source of BDNF in the retina. Furthermore, induction of BDNF expression by adrenergic agonists may provide a therapeutic approach to retinal neurodegenerative disorders.

Animals↗
PubMed2005

Influences of dopaminergic lesion on epidermal growth factor-ErbB signals in Parkinson's disease and its model: neurotrophic implication in nigrostriatal neurons.

Epidermal growth factor (EGF) is a member of a structurally related family containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that exerts neurotrophic activity on midbrain dopaminergic neurons. To examine neurotrophic abnormality in Parkinson's disease (PD), we measured the protein content of EGF, TGFalpha, and HB-EGF in post-mortem brains of patients with Parkinson's disease and age-matched control subjects. Protein levels of EGF and tyrosine hydroxylase were decreased in the prefrontal cortex and the striatum of patients. In contrast, HB-EGF and TGFalpha levels were not significantly altered in either region. The expression of EGF receptors (ErbB1 and ErbB2, but not ErbB3 or ErbB4) was down-regulated significantly in the same forebrain regions. The same phenomenon was mimicked in rats by dopaminergic lesions induced by nigral 6-hydroxydopamine infusion. EGF and ErbB1 levels in the striatum of the PD model were markedly reduced on the lesioned side, compared with the control hemisphere. Subchronic supplement of EGF in the striatum of the PD model locally prevented the dopaminergic neurodegeration as measured by tyrosine hydroxylase immunoreactivity. These findings suggest that the neurotrophic activity of EGF is maintained by afferent signals of midbrain dopaminergic neurons and is impaired in patients with Parkinson's disease.

Adrenergic Agents↗
PubMed2004

Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites.

In neurons, perisynaptic or dendritic translation is implicated in synapse-wide alterations of function and morphology triggered by neural activity. The molecular mechanisms controlling local translation activation, however, have yet to be elucidated. Here, we show that local protein synthesis and translational activation in neuronal dendrites are upregulated by brain-derived neurotrophic factor (BDNF) in a rapamycin and small interfering RNA specific for mammalian target of rapamycin (mTOR)-sensitive manner. In parallel, BDNF induced the phosphorylation of tuberin and the activation of mTOR in dendrites and the synaptoneurosome fraction. mTOR activation stimulated translation initiation processes involving both eIF4E/4E-binding protein (4EBP) and p70S6 kinase/ribosomal S6 protein. BDNF induced phosphorylation of 4EBP in isolated dendrites. Moreover, local puff application of BDNF to dendrites triggered S6 phosphorylation in a restricted area. Taken together, these data indicate that mTOR-dependent translation activation is essential for the upregulation of local protein synthesis in neuronal dendrites.

Animals↗
PubMed2004

Involvement of brain-derived neurotrophic factor in early retinal neuropathy of streptozotocin-induced diabetes in rats: therapeutic potential of brain-derived neurotrophic factor for dopaminergic amacrine cells.

Although neurotrophins have been assessed as candidate therapeutic agents for neural complications of diabetes, their involvement in diabetic retinopathy has not been fully characterized. We found that the protein and mRNA levels of brain-derived neurotrophic factor (BDNF) in streptozotocin-induced diabetic rat retinas were reduced to 49% (P < 0.005) and 74% (P < 0.05), respectively, of those of normal control animals. In addition, dopaminergic amacrine cells appeared to be degenerating in the diabetic rat retinas, as revealed by tyrosine hydroxylase (TH) immunoreactivity. Overall TH protein levels in the retina were decreased to one-half that of controls (P < 0.01), reflecting reductions in the density of dopaminergic amacrine cells and the intensity of TH immunoreactivity within them. To confirm the neuropathological implications of BDNF reduction, we administered BDNF protein into the vitreous cavities of diabetic rats. Intraocular administration of BDNF rescued dopaminergic amacrine cells from neurodegeneration and counteracted the downregulation of TH expression, demonstrating its therapeutic potential. These findings suggest that the early retinal neuropathy of diabetes involves the reduced expression of BDNF and can be ameliorated by an exogenous supply of this neurotrophin.

Amacrine Cells↗
PubMed2003

Brain-derived neurotrophic factor signal enhances and maintains the expression of AMPA receptor-associated PDZ proteins in developing cortical neurons.

Postsynaptic molecules with PDZ domains (PDZ proteins) interact with various glutamate receptors and regulate their subcellular trafficking and stability. In rat neocortical development, the protein expression of AMPA-type glutamate receptor GluR1 lagged behind its mRNA expression and rather paralleled an increase in PDZ protein levels. One of the neurotrophins, brain-derived neurotrophic factor (BDNF), appeared to contribute to this process, regulating the PDZ protein expression. In neocortical cultures, BDNF treatment upregulated SAP97, GRIP1, and Pick1 PDZ proteins. Conversely, BDNF gene targeting downregulated these same PDZ molecules. The BDNF-triggered increases in PDZ proteins resulted in the elevation of their total association with the AMPA receptors GluR1 and GluR2/3, which led to the increase in AMPA receptor proteins. When Sindbis viruses carrying GluR1 or GluR2 C-terminal decoys disrupted their interactions, GluR2 C-terminal decoys inhibited both BDNF-triggered GluR1 and GluR2/3 increases, whereas GluR1 C-terminal decoys blocked only the BDNF-triggered GluR1 increase. In agreement, coexpression of SAP97 and GluR1 in nonneuronal HEK293 cells increased both proteins compared with their single transfection, implying mutual stabilization. This work reveals a novel function of BDNF in postsynaptic development by regulating the PDZ protein expression.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Experimental creation of a fully inseparable tripartite continuous-variable state.

A continuous-variable tripartite entangled state is experimentally generated by combining three independent squeezed vacuum states, and the variances of its relative positions and total momentum are measured. We show that the measured values violate the separability criteria based on the sum of these quantities and prove the full inseparability of the generated state.

Journal Article↗