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Kobe University, Toray Industries Inc, Tokyo Metropolitan Institute of Medical Science, University of Indonesia and Indonesian Institute of Sciences | Date: 2015-08-05

Provided are a HCV particle formation promoter capable of promoting formation of HCV particles in culture cells, and a method of enhancing production of HCV particles. Also provided are a method of evaluating an anti-HCV agent candidate substance, and a method of producing a HCV vaccine. The HCV particle formation promoter comprises as an active ingredient a statin or a pharmaceutically acceptable salt thereof. Addition of the statin or pharmaceutically acceptable salt thereof to HCV-infected culture cells can promote formation of infectious HCV particles and enhance production of the particles. In addition, an anti-HCV agent candidate substance is evaluated by culturing HCV-infected cells in the presence of the HCV particle formation promoter and the anti-HCV agent candidate substance. Further, a HCV vaccine is produced by using HCV particles produced by the method of enhancing production of HCV particles.

Tokyo Metropolitan Institute of Medical Science, Chugai Seiyaku Kabushiki Kaisha and Phoenixbio Co. | Date: 2015-03-04

The present invention provides a mouse with liver damage, having a high degree of damage against the mouses original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of:(i) transforming mouse ES cells with a DNA fragment containing a liver-specific promoter/enhancer and cDNA that encodes a urokinase-type plasminogen activator operably linked under the control thereof;(ii) injecting the transformed mouse ES cells obtained in step (i) into a host embryo;(iii) transplanting the host embryo obtained in step (ii) via the injection of the ES cells into the uterus of a surrogate mother mouse, so as to obtain a chimeric mouse; and(iv) crossing the chimeric mice obtained in step (iii), so as to obtain a transgenic mouse in which the DNA fragment is introduced in a heterozygous form.

Mizushima N.,Tokyo Medical and Dental University | Komatsu M.,Tokyo Metropolitan Institute of Medical Science
Cell | Year: 2011

Autophagy is the major intracellular degradation system by which cytoplasmic materials are delivered to and degraded in the lysosome. However, the purpose of autophagy is not the simple elimination of materials, but instead, autophagy serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Here we provide a multidisciplinary review of our current understanding of autophagy's role in metabolic adaptation, intracellular quality control, and renovation during development and differentiation. We also explore how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease. © 2011 Elsevier Inc.

Hasegawa M.,Tokyo Metropolitan Institute of Medical Science
Acta neuropathologica communications | Year: 2014

BACKGROUND: α-Synuclein is the major component of filamentous inclusions that constitute the defining characteristic of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, so-called α-synucleinopathies. Recent studies revealed that intracerebral injection of recombinant α-synuclein fibrils into wild-type mouse brains induced prion-like propagation of hyperphosphorylated α-synuclein pathology. However, the propagation mechanisms of α-synuclein have not been fully elucidated.RESULTS: In this study, in order to establish where and how α-synuclein pathology propagates, we injected recombinant mouse α-synuclein fibrils into three different brain areas (substantia nigra, striatum, and entorhinal cortex) of wild-type mice and compared the resulting distributions of α-synuclein pathology at 1 month after injection. Distinct patterns of pathology were observed in mice injected at the different sites. Within one month after injection, the pathology had spread to neurons in areas far from the injection sites, especially areas with direct neural connections to the injection sites. Surprisingly, phosphorylated tau and TDP-43 pathologies were also observed in mice injected with α-synuclein fibrils into striatum and entorhinal cortex at one month after injection. Phosphorylated tau and TDP-43 were accumulated in dot-like inclusions, but these were rarely colocalized with α-synuclein pathology. It seems that accumulation of α-synuclein has a synergistic effect on tau and TDP-43 aggregation. Additionally, intracerebral injection with sarkosyl-insoluble fraction prepared from wild-type mice injected synthetic α-synuclein fibrils can also induce phosphorylated α-synuclein pathology in wild-type mice.CONCLUSIONS: Our data indicate that α-synuclein aggregation spread by prion-like mechanisms through neural networks in mouse brains.

Akiyama H.,Tokyo Metropolitan Institute of Medical Science
Acta neuropathologica communications | Year: 2014

BACKGROUND: Tangle-predominant dementia (TPD) is characterized neuropathologically by numerous neurofibrillary tangles in the limbic areas with no or occasional senile plaques throughout the brain. TPD is an under-recognized disease, while it is a common cause of dementia in those over 80 years of age. In the present study, we describe hyperphosphorylated tau (tau) accumulation in the nucleus accumbens (Acb) in patients with TPD.RESULTS: We investigated immunohistochemically the brain tissues from 7 patients with TPD, 22 with Alzheimer disease (AD) and 11 non-demented aged subjects. In the Acb of all 7 TPD patients, a considerable number of tau positive neurons were found together with many neuropil threads. The tau deposits in the Acb were labeled with all the anti-tau antibodies used in the present study. They included conformational change-specific, phosphorylation-specific and phosphorylation-independent antibodies. The Acb consists of the predominant medium-sized neurons with a small number of large neurons. Both the cell types were affected by tau pathology in TPD. Tau accumulation in the majority of such neurons appeared to be pretangle-like, diffuse deposits with only occasional paired helical filament formation. Tau positive neurons were also found in the Acb in some AD and non-demented aged subjects but much fewer in the majority of cases. The immunoblot analyses of fresh frozen samples of the Acb and parahippocampal cortex from 3 TPD and 3 AD patients revealed that the insoluble tau in the Acb was a mixture of the 3- and 4-repeat isoforms.CONCLUSIONS: To our knowledge, this is the first report on the occurrence of tau accumulation in the Acb in TPD. The Acb receives direct and massive projections from the hippocampal CA1 and subiculum where neurofibrillary tangles are known to occur more frequently in TPD than in AD. The prevalence of abnormal tau accumulation in the Acb in TPD may support the idea that abnormal tau aggregation propagates via neural circuits. In all but one TPD cases used in this study, delusion was a consistent clinical feature. Whether the Acb tau accumulation is related to the psychiatric symptoms in TPD may be an issue for further investigation.

Komatsu M.,Tokyo Metropolitan Institute of Medical Science
Autophagy | Year: 2011

p62 is a ubiquitously expressed cellular protein conserved in metazoa but not in plants and fungi, and is known as one of the selective substrates for autophagy. This protein is localized at the autophagosome formation site and directly interacts with LC3, an autophagosomelocalizing protein, and it is incorporated subsequently into the autophagosome and finally degraded. Impaired autophagy is accompanied by the accumulation of p62, followed by the formation of aggregates positive for p62 and ubiquitinated proteins because of the nature of both self-oligomerization and the ubiquitinbinding capacity of p62. The p62-positive aggregates observed in hepatocytes of liver-specific Atg7-deficient mice are completely dispersed by additional loss of p62, suggesting the involvement of p62 in the formation of disease-related inclusion bodies. Importantly, similar aggregates known as Mallory bodies and intracellular hyaline bodies have been identified in hepatocellular carcinoma (HCC). However, the pathophysiological significance of such aggregates remains unclear. Recently, we identified the role of p62-positive aggregates in human HCC and autophagy-deficient tumors in tumor development through persistent activation of Nrf2, a transcription factor responsible for stress response. © 2011 Landes Bioscience.

Tokyo Metropolitan Institute of Medical Science | Date: 2016-09-21

An object of the present invention is to provide a method for efficiently identifying a polyubiquitinated substrate which is generally not easily identified. The method for identifying a polyubiquitinated substrate includes (1) a step of expressing a trypsin-resistant polyubiquitin chain-binding protein and a ubiquitin ligase in a cell, (2) a step of isolating a complex that contains the trypsin-resistant polyubiquitin chain-binding protein from the cell having undergone the step (1), (3) a step of subjecting the complex isolated by the step (2) to trypsin digestion, and (4) a step of identifying a peptide that has a ubiquitination site from a digested material obtained by the step (3).

Tokyo Metropolitan Institute of Medical Science | Date: 2016-03-09

The present invention has an objective of evaluating a motor function of a subject with a neurodegenerative disease with high accuracy using a motor function analysis system that utilizes a wrist joint movement of the subject. The motor function analysis system 1 of the present invention comprises: a display unit 3 for displaying image information including a moving target image and a cursor image 11 for tracking the target image; a moving unit 4 used by the subject to move the cursor image 11; and an analyzer 7 for detecting the tracking status of the target image tracked by the cursor image and analyzing the frequency of the movement components contained in the tracking status.

Tokyo Metropolitan Institute of Medical Science | Date: 2015-02-13

A antibody has as a target molecule a ubiquitin protein comprising a phosphorylated serine residue at position 65. In addition, a method is provided for specifically detecting Parkinsons disease at an early stage, in which a target molecule is a ubiquitin protein comprising a phosphorylated serine residue at position 65, a pharmaceutical composition for definitively treating or preventing Parkinsons disease, and a method for screening for the pharmaceutical composition.

Tokyo Metropolitan Institute of Medical Science | Date: 2015-07-09

The present invention provides antibodies useful for diagnosing and treating tumors as well as methods of screening for antitumor agents . More specifically, tumors can be diagnosed and treated using an anti-phosphorylated p62 antibody that recognizes phosphorylation of serine at position 351 of an amino acid sequence of SEQ ID No. 1 or at a position corresponding thereto. An antitumor agent can be obtained by screening for a substance that inhibits the phosphorylation or that dephosphorylates the phosphorylated serine.

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