National Center Hospital for Mental

Tokyo, Japan

National Center Hospital for Mental

Tokyo, Japan
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Miyake K.,Yamanashi University | Yang C.,Yamanashi University | Minakuchi Y.,National Institute of Genetics | Ohori K.,Yamanashi University | And 13 more authors.
PLoS ONE | Year: 2013

Monozygotic (identical) twins have been widely used in genetic studies to determine the relative contributions of heredity and the environment in human diseases. Discordance in disease manifestation between affected monozygotic twins has been attributed to either environmental factors or different patterns of X chromosome inactivation (XCI). However, recent studies have identified genetic and epigenetic differences between monozygotic twins, thereby challenging the accepted experimental model for distinguishing the effects of nature and nurture. Here, we report the genomic and epigenomic sequences in skin fibroblasts of a discordant monozygotic twin pair with Rett syndrome, an X-linked neurodevelopmental disorder characterized by autistic features, epileptic seizures, gait ataxia and stereotypical hand movements. The twins shared the same de novo mutation in exon 4 of the MECP2 gene (G269AfsX288), which was paternal in origin and occurred during spermatogenesis. The XCI patterns in the twins did not differ in lymphocytes, skin fibroblasts, and hair cells (which originate from ectoderm as does neuronal tissue). No reproducible differences were detected between the twins in single nucleotide polymorphisms (SNPs), insertion-deletion polymorphisms (indels), or copy number variations. Differences in DNA methylation between the twins were detected in fibroblasts in the upstream regions of genes involved in brain function and skeletal tissues such as Mohawk Homeobox (MKX), Brain-type Creatine Kinase (CKB), and FYN Tyrosine Kinase Protooncogene (FYN). The level of methylation in these upstream regions was inversely correlated with the level of gene expression. Thus, differences in DNA methylation patterns likely underlie the discordance in Rett phenotypes between the twins. © 2013 Miyake et al.


Adachi N.,Adachi Mental Clinic | Adachi N.,National Center Hospital for Mental | Onuma T.,National Center Hospital for Mental | Kato M.,National Center Hospital for Mental | And 6 more authors.
Epilepsia | Year: 2011

Purpose: Patients with recurrent epileptic seizures after the development of psychosis (Psychosis-Epilepsy) have been regarded as belonging to a different clinical entity from those with epilepsy antedating the development of psychosis (Epilepsy-Psychosis). However, clinical characteristics of patients with Psychosis-Epilepsy have not been well described, except for early German studies. We aimed to estimate the reliability of distinction between Psychosis-Epilepsy and Epilepsy-Psychosis by comparing their clinical characteristics. Methods: Among 312 patients with epilepsy and psychosis enrolled in this multicenter study, 23 patients had Psychosis-Epilepsy and 289 patients had Epilepsy-Psychosis (i.e., interictal psychosis). Demographic (i.e., sex, age at time of evaluation, and intellectual functioning), psychiatric (i.e., age at onset of psychosis, subtype of psychosis, duration of psychotic episode, and a family history of psychosis), and epileptic (i.e., age at onset of epilepsy, subtype of epilepsy, seizure type, and a family history of epilepsy) characteristics of both groups were compared. Key Findings: Clinical characteristics, either in their psychoses or epilepsies, except for age-related variables, were equivalent between patients with Psychosis-Epilepsy and those with Epilepsy-Psychosis. Time intervals between onset of psychosis and that of epilepsy in the two groups showed a normal distribution curve. Significance: The presence of many common features and the linear distribution of the time intervals did not fully support that Psychosis-Epilepsy and Epilepsy-Psychosis were two distinctly different entities. Among certain patients who have genetic vulnerabilities to both psychoses and seizures, psychosis may develop either antedating or postdating the development of epilepsy. These findings may suggest a necessary reconceptualization of psychoses in epilepsy. © 2011 International League Against Epilepsy.


Adachi N.,Adachi Mental Clinic | Adachi N.,National Center Hospital for Mental | Akanuma N.,National Center Hospital for Mental | Akanuma N.,Tokyo Medical and Dental University | And 7 more authors.
British Journal of Psychiatry | Year: 2010

Background: Age at the first psychotic episode and an interval between the onset of epilepsy and that of psychosis reflect developmental processes of interictal psychosis. However, factors relating to these indices remain unknown. Aims: To identify clinical variables that are associated with the timing of the development of interictal psychosis. Method: In 285 adults with epilepsy with interictal psychosis, effects of epileptic (epilepsy type), organic (intellectual functioning) and genetic (family history of psychosis) variables on timing of the development of psychosis were examined. Results: The mean interval between the onset of epilepsy and that of psychosis was 14.4 years. Some psychosis occurred within a few years of the first seizure. Generalised epilepsy, normal intellectual function and a positive family history of psychosis were associated with early onset of psychosis. Conclusions: Early development of interictal psychosis in people with epilepsy may reflect other individual vulnerabilities to psychosis rather than epilepsy-related damage.


Konno M.,Tohoku University | Hasegawa T.,Tohoku University | Baba T.,Tohoku University | Miura E.,Tohoku University | And 7 more authors.
Molecular Neurodegeneration | Year: 2012

Background: The intracellular deposition of misfolded proteins is a common neuropathological hallmark of most neurodegenerative disorders. Increasing evidence suggests that these pathogenic proteins may spread to neighboring cells and induce the propagation of neurodegeneration. Results: In this study, we have demonstrated that -synuclein (SYN), a major constituent of intracellular inclusions in synucleinopathies, was taken up by neuronal and oligodendroglial cells in both a time- and concentration-dependent manner. Once incorporated, the extracellular SYN was immediately assembled into high-molecular-weight oligomers and subsequently formed cytoplasmic inclusion bodies. Furthermore, SYN uptake by neurons and cells of the oligodendroglial lineage was markedly decreased by the genetic suppression and pharmacological inhibition of the dynamin GTPases, suggesting the involvement of the endocytic pathway in this process. Conclusions: Our findings shed light on the mode of SYN uptake by neuronal and oligodendroglial cells and identify therapeutic strategies aimed at reducing the propagation of protein misfolding. © 2012 Konno et al.; licensee BioMed Central Ltd.


Hasegawa T.,Tohoku University | Baba T.,Tohoku University | Kobayashi M.,Tohoku University | Konno M.,Tohoku University | And 5 more authors.
Neurochemistry International | Year: 2010

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder presenting variable combinations of parkinsonism, cerebellar ataxia, corticospinal and autonomic dysfunction. Alpha-synuclein (α-SYN)- immunopositive glial cytoplasmic inclusions (GCIs) represent the neuropathological hallmark of MSA, and tubulin polymerization promoting protein (TPPP)/p25 in oligodendroglia has been known as a potent stimulator of α-SYN aggregation. To gain insight into the molecular pathomechanisms of GCI formation and subsequent oligodendroglial degeneration, we ectopically expressed α-SYN and TPPP in HEK293T and oligodendroglial KG1C cell lines. Here we showed that TPPP specifically accelerated α-SYN oligomer formation and co-immunoprecipitation analysis revealed the specific interaction of TPPP and α-SYN. Moreover, phosphorylation of α-SYN at Ser-129 facilitated the TPPP-mediated α-SYN oligomerization. TPPP facilitated α-SYN-positive cytoplasmic perinuclear inclusions mimicking GCI in both cell lines; however, apoptotic cell death was only observed in KG1C cells. This apoptotic cell death was partly rescued by sirtuin 2 (SIRT2) inhibition. Together, our results provide further insight into the molecular pathogenesis of MSA and potential therapeutic approaches. © 2010 Published by Elsevier Ltd.


Hasegawa T.,Tohoku University | Konno M.,Tohoku University | Baba T.,Tohoku University | Sugeno N.,Tohoku University | And 13 more authors.
PLoS ONE | Year: 2011

Many neurodegenerative diseases share a common pathological feature: the deposition of amyloid-like fibrils composed of misfolded proteins. Emerging evidence suggests that these proteins may spread from cell-to-cell and encourage the propagation of neurodegeneration in a prion-like manner. Here, we demonstrated that α-synuclein (αSYN), a principal culprit for Lewy pathology in Parkinson's disease (PD), was present in endosomal compartments and detectably secreted into the extracellular milieu. Unlike prion protein, extracellular αSYN was mainly recovered in the supernatant fraction rather than in exosome-containing pellets from the neuronal culture medium and cerebrospinal fluid. Surprisingly, impaired biogenesis of multivesicular body (MVB), an organelle from which exosomes are derived, by dominant-negative mutant vacuolar protein sorting 4 (VPS4) not only interfered with lysosomal targeting of αSYN but facilitated αSYN secretion. The hypersecretion of αSYN in VPS4-defective cells was efficiently restored by the functional disruption of recycling endosome regulator Rab11a. Furthermore, both brainstem and cortical Lewy bodies in PD were found to be immunoreactive for VPS4. Thus, VPS4, a master regulator of MVB sorting, may serve as a determinant of lysosomal targeting or extracellular secretion of αSYN and thereby contribute to the intercellular propagation of Lewy pathology in PD. © 2011 Hasegawa et al.


Sakuma H.,National Center Hospital for Mental | Awaya Y.,Seibo International Catholic Hospital | Shiomi M.,Osaka City General Hospital | Yamanouchi H.,Dokkyo University | And 4 more authors.
Acta Neurologica Scandinavica | Year: 2010

Objective - We conducted a nationwide multicenter study in Japan to elucidate the clinical and laboratory characteristics of acute encephalitis with refractory, repetitive partial seizures (AERRPS). Materials and methods - Clinical and laboratory features, treatment, and outcome were assessed using a structured questionnaire. Results - Twenty-nine children were enrolled in the study. Refractory and repetitive partial seizures accompanied by fever were the cardinal clinical features. Partial seizures consisted principally of eye deviation or facial twitching, being periodically repeated during the acute phase. These seizures were refractory to conventional anticonvulsants and were only suppressed by high-dose intravenous barbiturate administration. Rhythmic activities on electroencephalography and non-specific cerebral atrophy on neuroimaging were common. Serum or cerebrospinal antibodies against GluRε2 were positive in six patients. General prognosis was unfavorable due to intractable epilepsy and cognitive deficits. Conclusion - Based on the peculiar and homogenous features, AERRPS can be regarded as a distinct clinical entity. © 2009 Blackwell Munksgaard.


Sakuma H.,National Center Hospital for Mental | Sugai K.,National Center Hospital for Mental | Sasaki M.,National Center Hospital for Mental
Pediatric Neurology | Year: 2010

Limbic encephalitis not associated with malignancy was investigated in Japanese children, with particular focus on clinical features distinct from adult cases. Clinical, laboratory, and radiographic findings were studied in pediatric nonparaneoplastic limbic encephalitis, based on a literature review and questionnaire-based analyses. Analysis of 14 cases revealed the predominance of seizure occurrence, disturbance in consciousness, and frequent extralimbic signs. The majority manifested antecedent febrile illnesses, suggesting the involvement of infection-induced autoimmunity targeted to neuronal antigens. These clinical observations indicate a child-specific phenotype of limbic encephalitis. Further studies on its immunopathogenesis are needed to determine whether childhood limbic encephalitis is a distinct subcategory. © 2010 by Elsevier Inc. All rights reserved.


Shiga A.,Niigata University | Nozaki H.,Niigata University | Yokoseki A.,Niigata University | Nihonmatsu M.,Niigata University | And 13 more authors.
Human Molecular Genetics | Year: 2011

Cerebral small-vessel disease is a common disorder in elderly populations; however, its molecular basis is not well understood. We recently demonstrated that mutations in the high-temperature requirement A (HTRA) serine peptidase 1 (HTRA1) gene cause a hereditary cerebral small-vessel disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). HTRA1 belongs to the HTRA protein family, whose members have dual activities as chaperones and serine proteases and also repress transforming growth factor-β (TGF-β) family signaling. We demonstrated that CARASIL-associated mutant HTRA1s decrease protease activity and fail to decrease TGF-β family signaling. However, the precise molecular mechanism for decreasing the signaling remains unknown. Here we show that increased expression of ED-A fibronectin is limited to cerebral small arteries and is not observed in coronary, renal arterial or aortic walls in patients with CARASIL. Using a cell-mixing assay, we found that HTRA1 decreases TGF-β1 signaling triggered by proTGF-β1 in the intracellular space. HTRA1 binds and cleaves the pro-domain of proTGF-β1 in the endoplasmic reticulum (ER), and cleaved proTGF-β1 is degraded by ER-associated degradation. Consequently, the amount of mature TGF-β1 is reduced. These results establish a novel mechanism for regulating the amount of TGF-β1, specifically, the intracellular cleavage of proTGF-b1 in the ER. © The Author 2011. Published by Oxford University Press. All rights reserved.


Sekimoto M.,National Center Hospital for Mental | Kato M.,National Center Hospital for Mental | Watanabe T.,National Center Hospital for Mental | Kajimura N.,National Center Hospital for Mental | Takahashi K.,National Center Hospital for Mental
Schizophrenia Research | Year: 2011

Background: Delta sleep is mediated by thalamocortical circuits and is postulated to be abnormal in schizophrenia. Delta wave deficits during sleep have been observed in patients with schizophrenia. Negative symptoms have been reported to reflect frontal lobe dysfunction and to be associated with decreased delta wave sleep. This investigation was undertaken to identify cortical functional abnormalities in patients with schizophrenia shown on the electroencephalogram. Methods: We compared seventeen male, medically treated or neuroleptic-naive outpatients with schizophrenia and 18 healthy male volunteers by all-night polysomnography and investigated cortical regional differences of delta waves. All-night sleep data was evaluated by period amplitude analyses. Delta waves during sleep were investigated in bilateral frontal, central, parietal, and occipital regions by computer analysis. The associations between delta waves in all regions and measures of clinical variables were also estimated. Results: Patients with schizophrenia showed lower total delta wave counts during all-night sleep than did control subjects in all regions. Control subjects showed significantly higher delta wave counts in the right frontal and central region than in the left, which was not observed in patients with schizophrenia. Significant inverse correlations were observed between negative symptom scores and delta wave counts in all regions. Control subjects showed significant inverse correlations between delta wave counts and age, which were not identified in patients with schizophrenia. Conclusions: Delta wave deficits in all regions may reflect thalamocortical dysfunction in schizophrenia. Reduced right frontal and central delta wave dominance is suggested to be involved in the pathophysiology of schizophrenia. © 2010 Elsevier B.V.

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