Biomedical subjects

Yuji Ozeki

Publications and source records attributed to Yuji Ozeki.

11 recordsLinked to original sources

PubMed2006

DISC1 immunoreactivity at the light and ultrastructural level in the human neocortex.

Disrupted-In-Schizophrenia 1 (DISC1) is one of two genes that straddle the chromosome 1 breakpoint of a translocation associated with an increased risk of schizophrenia. DISC1 has been identified in the brain of various mammalian species, but no previous immunocytochemical studies have been conducted in human neocortex. We examined DISC1 immunoreactivity in frontal and parietal cortex (BA 4, 9, 39, and 46) in normal human brain. At the light microscopic level, immunolabeling was prominent in the neuropil, in multiple populations of cells, and in the white matter. At the ultrastructural level, staining was prominent in structures associated with synaptic function. Immunolabeled axon terminals comprised 8% of all terminals and formed both asymmetric and symmetric synapses. Labeled axon terminals formed synapses with labeled spines and dendrites; in some, only the postsynaptic density (PSD) of the postsynaptic structure was labeled. The most common configuration, however, was an unlabeled axon terminal forming an asymmetric synapse with a spine that had immunoreactivity deposited on the PSD and throughout the spine. The presence of DISC1 in multiple types of synapses suggests the involvement of DISC1 in corticocortical as well as thalamocortical connections. Staining was also present in ribosomes, parts of the chromatin, in dendritic shafts, and on some microtubules. Labeling was absent from the Golgi apparatus and multivesicular bodies, which are associated with protein excretion. These anatomical localization data suggest that DISC1 participates in synaptic activity and microtubule function, and are consistent with the limited data on its adult function.

Adult↗

PubMed2005

A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development.

Disrupted-In-Schizophrenia-1 (DISC1), originally identified at the breakpoint of a chromosomal translocation that is linked to a rare familial schizophrenia, has been genetically implicated in schizophrenia in other populations. Schizophrenia involves subtle cytoarchitectural abnormalities that arise during neurodevelopment, but the underlying molecular mechanisms are unclear. Here, we demonstrate that DISC1 is a component of the microtubule-associated dynein motor complex and is essential for maintaining the complex at the centrosome, hence contributing to normal microtubular dynamics. Carboxy-terminal-truncated mutant DISC1 (mutDISC1), which results from a chromosomal translocation, functions in a dominant-negative manner by redistributing wild-type DISC1 through self-association and by dissociating the DISC1-dynein complex from the centrosome. Consequently, either depletion of endogenous DISC1 or expression of mutDISC1 impairs neurite outgrowth in vitro and proper development of the cerebral cortex in vivo. These results indicate that DISC1 is involved in cerebral cortex development, and suggest that loss of DISC1 function may underlie neurodevelopmental dysfunction in schizophrenia.

Animals↗

PubMed2005

S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) influences cytotoxicity, translocating to the nucleus during apoptosis. Here we report a signalling pathway in which nitric oxide (NO) generation that follows apoptotic stimulation elicits S-nitrosylation of GAPDH, which triggers binding to Siah1 (an E3 ubiquitin ligase), nuclear translocation and apoptosis. S-nitrosylation of GAPDH augments its binding to Siah1, whose nuclear localization signal mediates translocation of GAPDH. GAPDH stabilizes Siah1, facilitating its degradation of nuclear proteins. Activation of macrophages by endotoxin and of neurons by glutamate elicits GAPDH-Siah1 binding, nuclear translocation and apoptosis, which are prevented by NO deletion. The NO-S-nitrosylation-GAPDH-Siah1 cascade may represent an important molecular mechanism of cytotoxicity.

Animals↗

PubMed2005

Selective chemical vapor deposition synthesis of double-wall carbon nanotubes on mesoporous silica.

Double-wall carbon nanotubes (DWNTs) have been selectively synthesized over Fe/Co loaded mesoporous silica by catalytic chemical vapor deposition of alcohol. Several silica materials with desired pore diameter and morphology have been investigated for the DWNT growth. The diameter distribution and selectivity of the DWNT are found to depend on the reaction temperature, pore size, and thermal stability of the support material. A high-yield synthesis of DWNTs has been achieved at 900 degrees C over high-temperature stable mesoporous silica. The outer diameter of DWNTs is found to be in the range of 1.5-5.4 nm with a "d" spacing of 0.38 +/- 0.02 nm between inner and outer layers, which is much larger than those of multiwall carbon nanotubes.

Alcohols↗

PubMed2005

A form of DISC1 enriched in nucleus: altered subcellular distribution in orbitofrontal cortex in psychosis and substance/alcohol abuse.

Disrupted-In-Schizophrenia 1 (DISC1) was identified as the sole gene whose ORF is truncated and cosegregates with major mental illnesses in a Scottish family. DISC1 has also been suggested, by association and linkage studies, to be a susceptibility gene for schizophrenia (SZ) in independent populations. However, no analysis of DISC1 protein in human brains, especially those of patients with SZ, has yet been conducted. Here we performed a biochemical analysis of DISC1 protein in a well characterized set of autopsied brains, including brains of patients with SZ, bipolar disorder, and major depression (MD), as well as normal control brains. We identified an isoform of DISC1 by using MS and demonstrated that it is enriched in the nucleus of HeLa cells. In the orbitofrontal cortex, the subcellular distribution of this DISC1 isoform, assessed by the nuclear to cytoplasmic ratio in the immunoreactivity of the isoform, is significantly changed in brains from patients with SZ and MD. This altered distribution is also observed in those subjects with substance and alcohol abuse. The changes in MD brains are significantly influenced by substance/alcohol abuse as well as postmortem interval; however, the alteration in SZ brains is free from brain-associated confounding factors, although an interaction with substance/alcohol abuse cannot be completely ruled out. These results suggest that DISC1 may be implicated in psychiatric conditions in other populations than the unique Scottish family.

Alcoholism↗

PubMed2005

Huntingtin is cleaved by caspases in the cytoplasm and translocated to the nucleus via perinuclear sites in Huntington's disease patient lymphoblasts.

Accumulation of mutant Huntingtin (Htt), especially the N-terminal-cleaved Htt, participates in the pathophysiology of Huntington's disease (HD). It is difficult to elucidate temporal properties of the translocation of "endogenous" Htt using autopsy HD patient brains. Thus, we examined the cell biology of "endogenous" Htt cleavage and nuclear translocation in cultured lymphoblasts of HD patients and controls. Apoptotic stimulation of lymphoblasts elicits caspase-dependent cleavage and selective nuclear translocation of N-terminal portions of Htt. Discrete clusters of the N-terminal Htt accumulate at unique perinuclear sites prior to nuclear translocation. Our findings suggest that caspase cleavage of Htt is cytoplasmic and precedes sorting to specific perinuclear sites followed by nuclear translocation in HD patient tissue.

Active Transport, Cell Nucleus↗

PubMed2004

A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders.

Recent studies have shown that functional variations in clock genes, which generate circadian rhythms through interactive positive/negative feedback loops, contribute to the development of circadian rhythm sleep disorders in humans. Another potential candidate for rhythm disorder susceptibility is casein kinase I epsilon (CKIepsilon), which phosphorylates clock proteins and plays a pivotal role in the circadian clock. To determine whether variations in CKIepsilon induce vulnerability to human circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake syndrome (N-24), we analyzed all of the coding exons of the human CKIepsilon gene. One of the variants identified encoded an amino-acid substitution S408N, eliminating one of the putative autophosphorylation sites in the carboxyl-terminal extension of CKIepsilon. The N408 allele was less common in both DSPS (p = 0.028) and N-24 patients (p = 0.035) compared to controls. When DSPS and N-24 subjects were combined, based on an a priori prediction of a common mechanism underlying both DSPS and N-24, the inverse association between the N408 allele and rhythm disorders was highly significant (p = 0.0067, odds ratio = 0.42, 95% confidence interval: 0.22-0.79). In vitro kinase assay revealed that CKIepsilon with the S408N variation was approximately 1.8-fold more active than wild-type CKIepsilon. These results indicate that the N408 allele in CKIepsilon plays a protective role in the development of DSPS and N-24 through alteration of the enzyme activity.

Adult↗

PubMed2004

[DISC1 and schizophrenia].

Molecular mechanisms underlying the pathogenesis of schizophrenia remains elusive. The difficulty in accessing the mechanisms stems from, at least in part, multiple etiologies for schizophrenia. We have studied DISC1, as it was identified as a candidate gene for a schizophrenia-associated mental condition with the single etiology. Thus far, we have obtained evidence that DISC1 may have implications in neurodevelopment. This concept fits with many historical observations found for schizophrenia in association with neurodevelopmental abnormalities. DISC1 may become one of the key molecules in studying the pathogenesis of schizophrenia.

Animals↗

PubMed2003

Mutation screening of the human period 2 gene in bipolar disorder.

We tested whether the human period 2 gene (hper2), one of the essential components of the circadian oscillator, might have influence on bipolar disorder. We screened 88 bipolar disorder patients and 127 controls, all of Japanese origin. Screening in the casein kinase I epsilon (CKIepsilon) binding region of hper2, which was previously reported in familial advanced sleep-phase syndrome patients, with polymerase chain reaction amplification revealed four polymorphisms. One of the four polymorphisms had an amino acid substitution of a serine at 662 with a glycine (S662G). The frequencies of the S662G allele and genotypes on patients with bipolar disorder were very low and had no difference from those in controls. Polymorphism on the CKIepsilon binding region of hper2 gene which was previously reported, is unlikely to play an important role in the development of bipolar disorder.

Adolescent↗

PubMed2002

Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth.

Disrupted-in-Schizophrenia-1 (DISC-1) is a gene whose mutant truncation is associated with major psychiatric illness with a predominance of schizophrenic symptomatology. We have cloned and characterized rodent DISC-1. DISC-1 expression displays pronounced developmental regulation with the highest levels in late embryonic life when the cerebral cortex develops. In yeast two-hybrid analyses, DISC-1 interacts with a variety of cytoskeletal proteins. One of these, NudE-like (NUDEL), is associated with cortical development and is linked to LIS-1, the disease gene for a form of lissencephaly, a disorder of cortical development. The disease mutant form of DISC-1 fails to bind NUDEL. Expression of mutant, but not wild-type, DISC-1 in PC12 cells reduces neurite extension. As schizophrenia is thought to reflect defects in cortical development that are determined by cytoskeletal protein activities, the cellular disturbances we observe with mutant DISC-1 may be relevant to psychopathologic mechanisms.

Animals↗

PubMed2002

Mutation screening of the human Clock gene in circadian rhythm sleep disorders.

We tested whether the human Clock (hClock) gene, one of the essential components of the circadian oscillator, is implicated in the vulnerability to delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake syndrome (N-24). Screening in the entire coding region of the hClock gene with PCR amplification revealed three polymorphisms, of which two predicted the amino acid substitutions R533Q and H542R. The frequencies of the R533Q and H542R alleles in patients with DSPS or N-24 were very low and not significantly different from those in control subjects. A T3111C polymorphism in the 3'-untranslated region of hClock, which had been reportedly associated with morning or evening preference for activity, was also investigated; the results showed that the 3111C allele frequency decreased in DSPS. Polymorphisms in the coding region of the hClock gene are unlikely to play an important role in the development of DSPS or N-24. The possible contribution of the T3111C polymorphism to DSPS susceptibility should be studied further.

Adult↗