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Nishi-Tokyo-shi, Japan

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.

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.

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.

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.

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