Updated on 2023/02/05

写真a

 
INOUE Keiichi
 
Organization
Academic Assembly Institute of Medicine and Dentistry Specially Appointed Assistant Professor
Graduate School of Medical and Dental Sciences Specially Appointed Assistant Professor
Title
Specially Appointed Assistant Professor
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Degree

  • 博士(農学) ( 2003.3   東京大学 )

Research Interests

  • Disease Model

  • Mitophagy

  • Human Fibroblast

  • Alzheimer's Disease

  • Parkinson's Disease

  • Beta Amyloid

  • サルコペニア

  • 遺伝子治療

  • ウイルスベクター

  • Autophagy

  • Neurodegenerative Disorders

  • CRISPR Transcriptional Activation

  • 遺伝子改変マウス

Research Areas

  • Life Science / Pathological biochemistry

  • Life Science / Pathophysiologic neuroscience

  • Life Science / Animal life science

  • Life Science / Laboratory animal science

  • Life Science / Medical biochemistry

Research History (researchmap)

  • Niigata University

    2021.9

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  • Niigata University   Graduate School of Medical and Dental Sciences   Specially Appointed Assistant Professor

    2018.12

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  • Prevail Therapeutics Inc   Senior Scientist

    2017.12 - 2018.12

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  • Columbia University College of Physicians & Surgeons   Department of Pathology & Cell Biology   Assistant Professor

    2016.7 - 2017.12

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  • Columbia University College of Physicians & Surgeons   Department of Pathology   Associate Research Scientist

    2010.7 - 2016.6

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  • New York Stem Cell Foundation (NYSCF)   Druckenmiller Fellow

    2007.7 - 2010.6

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  • Columbia University College of Physicians & Surgeons   Department of Pathology   Postdoctoral Research Fellow

    2007.7 - 2010.6

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  • Columbia University College of Physicians & Surgeons   Department of Pathology   Postdoctoral Research Scientist

    2005.4 - 2007.6

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  • Tokyo Medical and Dental University Medical Research Institute   Department of Molecular Pharmacology   Research Assistant

    2004.1 - 2005.3

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  • Tokyo Medical and Dental University Medical Research Institute   Department of Molecular Pharmacology

    2003.4 - 2004.1

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  • RIEKN Brain Science Institute   Labratory for Behaviroal Genetics   Trainee

    1998.3 - 2003.3

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  • Kyoto University Virus Research Institute   College Student

    1997.3 - 1998.3

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Research History

  • Niigata University   Institute of Medicine and Dentistry, Academic Assembly   Specially Appointed Assistant Professor

    2018.12

  • Niigata University   Graduate School of Medical and Dental Sciences   Specially Appointed Assistant Professor

    2018.12

Education

  • University of Tokyo   Graduate School of Agricultural and Life Sciences   Department of Animal Resource Sciences

    2000.4 - 2003.3

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  • University of Tokyo   Graduate School of Agricultural and Life Sciences   Department of Animal Resource Sciences

    1998.4 - 2000.3

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  • Kyoto University   Facility of Agriculture   Department of Animal Sciences

    1994.4 - 1998.3

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Professional Memberships

  • 日本オートファジーコンソーシアム

    2020.12

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  • THE JAPANESE BIOCHEMICAL SOCIETY

    2018.4

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  • THE JAPAN NEUROSCIENCE SOCIETY

    2001

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Qualification acquired

  • 3rd grade Certified Specialist of Intellectual Property Management(administration)

 

Papers

  • CRISPR-activated patient fibroblasts for modeling of familial Alzheimer's disease. Invited Reviewed

    Inoue K.

    Neuroscience Research.   172   7 - 12   2021.11

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  • Mitophagy reporter mouse analysis reveals increased mitophagy activity in disuse‐induced muscle atrophy. Reviewed

    Yamashita SI, Kyuuma M, Inoue K (co-first, corresponding), Hata Y, Kawada R, Yamabi M, Fujii Y, Sakagami J, Fukuda T, Furukawa F, Tsukamoto S, Kanki T.

    Journal of Cellular Physiology.   236   7612 - 7624   2021.5

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  • Association and dissociation between the mitochondrial Far complex and Atg32 regulate mitophagy. Reviewed

    Innokentev A, Furukawa K, Fukuda T, Saigusa T, Inoue K, Yamashita SI, Kanki T.

    eLife.   9   e63694   2020.12

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  • Atg43 tethers isolation membranes to mitochondria to promote starvation-induced mitophagy in fission yeast. Reviewed

    Fukuda T, Ebi Y, Saigusa T, Furukawa K, Yamashita SI, Inoue K, Kobayashi D, Yoshida Y, Kanki T

    eLife.   9   e61245   2020.11

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  • Gemcitabine induces Parkin-independent mitophagy through mitochondrial-resident E3 ligase MUL1-mediated stabilization of PINK1. Reviewed International journal

    Igarashi R, Yamashita SI, Yamashita T, Inoue K, Fukuda T, Fukuchi T, Kanki T.

    Scientific Reports.   10 ( 1 )   1465 - 1465   2020.1

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    Mitophagy plays an important role in the maintenance of mitochondrial homeostasis. PTEN-induced kinase (PINK1), a key regulator of mitophagy, is degraded constitutively under steady-state conditions. During mitophagy, it becomes stabilized in the outer mitochondrial membrane, particularly under mitochondrial stress conditions, such as in treatment with uncouplers, generation of excessive mitochondrial reactive oxygen species, and formation of protein aggregates in mitochondria. Stabilized PINK1 recruits and activates E3 ligases, such as Parkin and mitochondrial ubiquitin ligase (MUL1), to ubiquitinate mitochondrial proteins and induce ubiquitin-mediated mitophagy. Here, we found that the anticancer drug gemcitabine induces the stabilization of PINK1 and subsequent mitophagy, even in the absence of Parkin. We also found that gemcitabine-induced stabilization of PINK1 was not accompanied by mitochondrial depolarization. Interestingly, the stabilization of PINK1 was mediated by MUL1. These results suggest that gemcitabine induces mitophagy through MUL1-mediated stabilization of PINK1 on the mitochondrial membrane independently of mitochondrial depolarization.

    DOI: 10.1038/s41598-020-58315-w

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  • Glaucoma-associated mutations in the optineurin gene have limited impact on Parkin-dependent mitophagy. Reviewed

    Chernyshova K, Inoue K, Yamashita SI, Fukuchi T, Kanki T.

    Investigative Ophthalmology & Visual Science.   60 ( 10 )   3625 - 3635   2019.8

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  • CRISPR transcriptional activation analysis unmasks an occult γ-secretase processivity defect in familial Alzheimer's disease skin fibroblasts. Reviewed

    Keiichi Inoue, Luis M. A. Oliveira, Asa Abeliovich.

    CELL REPORTS   21 ( 7 )   1727 - 1736   2017.11

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:CELL PRESS  

    Mutations in presenilin (PSEN) 1 and 2, which encode components of the g-secretase (GS) complex, cause familial Alzheimer's disease (FAD). It is hypothesized that altered GS-mediated processing of the amyloid precursor protein (APP) to the Ab42 fragment, which is accumulated in diseased brain, may be pathogenic. Here, we describe an in vitro model system that enables the facile analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes. In FAD patient-derived fibroblast cultures, CRISPR activation of APP or BACE unmasked an occult processivity defect in downstream GS-mediated carboxypeptidase cleavage of APP, ultimately leading to higher Ab42 levels. These data suggest that, selectively in neurons, relatively high levels of BACE1 activity lead to substrate pressure on FAD-mutant GS complexes, promoting CNS Ab42 accumulation. Our results introduce an additional platform for analysis of neurological disease.

    DOI: 10.1016/j.celrep.2017.10.075

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  • LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts Reviewed

    Scientific Reports.   6 ( 29945 )   2016.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:NATURE PUBLISHING GROUP  

    Leucine-rich repeat kinase 2 (LRRK2) has been linked to several clinical disorders including Parkinson's disease (PD), Crohn's disease, and leprosy. Furthermore in rodents, LRRK2 deficiency or inhibition leads to lysosomal pathology in kidney and lung. Here we provide evidence that LRRK2 functions together with a second PD-associated gene, RAB7L1, within an evolutionarily conserved genetic module in diverse cellular contexts. In C. elegans neurons, orthologues of LRRK2 and RAB7L1 act coordinately in an ordered genetic pathway to regulate axonal elongation. Further genetic studies implicated the AP-3 complex, which is a known regulator of axonal morphology as well as of intracellular protein trafficking to the lysosome compartment, as a physiological downstream effector of LRRK2 and RAB7L1. Additional cell-based studies implicated LRRK2 in the AP-3 complex-related intracellular trafficking of lysosomal membrane proteins. In mice, deficiency of either RAB7L1 or LRRK2 leads to prominent age-associated lysosomal defects in kidney proximal tubule cells, in the absence of frank CNS pathology. We hypothesize that defects in this evolutionarily conserved genetic pathway underlie the diverse pathologies associated with LRRK2 in humans and in animal models.

    DOI: 10.1038/srep29945

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  • Coordinate regulation of mature dopaminergic axon morphology by macroautophagy and the PTEN signaling pathway. Reviewed

    Inoue K, Rispoli J, Yang L, MacLeod D, Beal MF, Klann E, Abeliovich A

    PLOS Genetics.   9 ( 10 )   e1003845   2013.10

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  • Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway Reviewed

    Keiichi Inoue, Joanne Rispoli, Hanoch Kaphzan, Eric Klann, Emily I. Chen, Jongpil Kim, Masaaki Komatsu, Asa Abeliovich.

    Molecular Neurodegeneration.   7 ( 48 )   2012.9

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:BIOMED CENTRAL LTD  

    Background: Macroautophagy is an evolutionarily conserved mechanism for bulk intracellular degradation of proteins and organelles. Pathological studies have implicated macroautophagy defects in human neurodegenerative disorders of aging including Alzheimer's disease and tauopathies. Neuronal deficiency of macroautophagy throughout mouse embryonic development results in neurodevelopmental defects and early postnatal mortality. However, the role of macroautophagy in mature CNS neurons, and the relationship with human disease neuropathology, remains unclear. Here we describe mice deficient in an essential macroautophagy component, Atg7, specifically within postnatal CNS neurons.
    Results: Postnatal forebrain-specific Atg7 conditional knockout (cKO) mice displayed age-dependent neurodegeneration and ubiquitin- and p62-positive inclusions. Phosphorylated tau was significantly accumulated in Atg7 cKO brains, but neurofibrillary tangles that typify end-stage human tauopathy were not apparent. A major tau kinase, glycogen synthase kinase 3 beta (GSK3 beta), was also accumulated in Atg7 cKO brains. Chronic pharmacological inhibition of tau phosphorylation, or genetic deletion of tau, significantly rescued Atg7-deficiency-mediated neurodegeneration, but did not suppress inclusion formation.
    Conclusions: These data elucidate a role for macroautophagy in the long-term survival and physiological function of adult CNS neurons. Neurodegeneration in the context of macroautophagy deficiency is mediated through a phospho-tau pathway.

    DOI: 10.1186/1750-1326-7-48

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  • Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Reviewed

    Doege CA, Inoue K, Yamashita T, Rhee DB, Travis S, Fujita R, Guarnieri P, Bhagat G, Vanti WB, Shih A, Levine RL, Nik S, Chen EI, Abeliovich A

    Nature.   488 ( 7413 )   652 - 655   2012.8

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    Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM)(1). iPSC reprogramming erases somatic epigenetic signatures-as typified by DNA methylation or histone modification at silent pluripotency loci-and establishes alternative epigenetic marks of embryonic stem cells (ESCs)(2). Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts(5-7), our data, and also studies of Tet2-mutant human tumour cells(8), argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.

    DOI: 10.1038/nature11333

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  • A microRNA feedback circuit in midbrain dopamine neurons. Reviewed

    Kim J, Inoue K, Ishii J, Vanti WB, Voronov SV, Murchison E, Hannon G, Abeliovich A.

    Science.   317 ( 5842 )   1220 - 1224   2007.8

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    MicroRNAs ( miRNAs) are evolutionarily conserved, 18- to 25- nucleotide, non-protein coding transcripts that posttranscriptionally regulate gene expression during development. miRNAs also occur in postmitotic cells, such as neurons in the mammalian central nervous system, but their function is less well characterized. We investigated the role of miRNAs in mammalian midbrain dopaminergic neurons ( DNs). We identified a miRNA, miR-133b, that is specifically expressed in midbrain DNs and is deficient in midbrain tissue from patients with Parkinson's disease. miR-133b regulates the maturation and function of midbrain DNs within a negative feedback circuit that includes the paired-like homeodomain transcription factor Pitx3. We propose a role for this feedback circuit in the fine-tuning of dopaminergic behaviors such as locomotion.

    DOI: 10.1126/science.1140481

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  • Instant Neurons: Directed Somatic Cell Reprogramming Models of Central Nervous System Disorders Invited Reviewed

    Liang Qiang, Keiichi Inoue, Asa Abeliovich

    Biological Psychiatry.   75 ( 12 )   945 - 951   2014.6

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    Nuclear transplantation, cell fusion, and induced pluripotent stem cell studies have revealed a surprising degree of plasticity in mature mammalian cell fates. Somatic cell reprogramming also has been achieved more recently by the directed conversion of nonneuronal somatic cells, such as skin fibroblasts, to neuronal phenotypes. This approach appears particularly applicable to the in vitro modeling of human neurologic disorders. Central nervous system neurons are otherwise difficult to obtain from patients with neurologic disorders; however, nonhuman models may not reflect patient pathology. Somatic cell reprogramming may afford models of nonfamilial "sporadic" neurologic disorders, which are likely caused by multiple interacting genetic and nongenetic factors. Directed somatic cell reprogramming, which does not pass through typical in vivo developmental stages, toward many mature neuronal phenotypes has now been described. This article reviews the field and discusses the potential utilities of such models, such as for the development of personalized medicine strategies.

    DOI: 10.1016/j.biopsych.2013.10.027

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  • A crucial role for matrix metalloproteinase 2 in osteocytic canalicular formation and bone metabolism. Reviewed

    Inoue K, Mikuni-Takagaki Y, Oikawa K, Itoh T, Inada M, Noguchi T, Park JS, Onodera T, Krane SM, Noda M, Itohara S.

    Journal of Biological Chemistry.   281 ( 44 )   33814 - 33824   2006.11

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    Extracellular matrix production and degradation by bone cells are critical steps in bone metabolism. Mutations of the gene encoding MMP-2, an extracellular matrix-degrading enzyme, are associated with a human genetic disorder characterized by subcutaneous nodules, arthropathy, and focal osteolysis. It is not known how the loss of MMP-2 function results in the pathology. Here, we show that Mmp2-/- mice exhibited opposing bone phenotypes caused by an impaired osteocytic canalicular network. Mmp2-/- mice showed decreased bone mineral density in the limb and trunk bones but increased bone volume in the calvariae. In the long bones, there was moderate disruption of the osteocytic networks and reduced bone density throughout life, whereas osteoblast and osteoclast function was normal. In contrast, aged but not young Mmp2-/- mice had calvarial sclerosis with osteocyte death. Severe disruption of the osteocytic networks preceded osteocyte loss in Mmp2 -/- calvariae. Successful transplantation of wild-type periosteum restored the osteocytic canalicular networks in the Mmp2-/- calvariae, suggesting local roles of MMP-2 in determining bone phenotypes. Our results indicate that MMP-2 plays a crucial role in forming and maintaining the osteocytic canalicular network, and we propose that osteocytic network formation is a determinant of bone remodeling and mineralization. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

    DOI: 10.1074/jbc.M607290200

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  • The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Reviewed

    MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A.

    Neuron.   52 ( 4 )   587 - 593   2006

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  • Impaired spermatogenesis and male fertility defects in CIZ/Nmp4-disrupted mice Reviewed

    T Nakamoto, A Shiratsuchi, H Oda, K Inoue, T Matsumura, M Ichikawa, T Saito, S Seo, K Maki, T Asai, T Suzuki, A Hangaishi, T Yamagata, S Aizawa, M Noda, Y Nakanishi, H Hirai

    GENES TO CELLS   9 ( 6 )   575 - 589   2004.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:BLACKWELL PUBLISHING LTD  

    CIZ (Cas interacting zinc finger protein), also called Nmp4 (nuclear matrix protein 4), is a nucleocytoplasmic shuttling transcription factor that regulates the expression of collagen and matrix metalloproteinases. CIZ/Nmp4 was originally cloned by its binding to p130(Cas), a focal adhesion protein, and was recently shown to suppress BMP2 (bone mophogenetic protein 2) signalling. To explore the physiological role of CIZ/Nmp4, we disrupted CIZ/Nmp4-gene by inserting beta-galactosidase and neomycin resistance genes into the 2nd exon of CIZ/Nmp4-gene, which is utilized by all the sequenced alternative forms. CIZ(-/-) mice were born and grew to adulthood. Although they tend to be smaller than wild-type mice, no pathological abnormality was observed except in the testis. Histological analysis of the testes revealed variable degrees of spermatogenic cell degeneration within the seminiferous tubules of CIZ(-/-) mice, resembling the histology of the 'Germinal-cell aplasia with focal spermatogenesis'. Some of the CIZ(-/-) male mice developed infertility. TUNEL assay on testis sections revealed an increased occurrence of apoptosis of spermatogenic cells in the testes of CIZ(-/-) mice. CIZ/Nmp4 was co-localized with Smad1 in the testis, suggesting that a disregulation of BMP signalling could cause these phenotypes. These results suggest that CIZ/Nmp4 plays roles in the progress and the maintenance of spermatogenesis.

    DOI: 10.1111/j.1365-2443.2004.00746.x

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  • Impairment of superoxide dismutase activation by N-terminally truncated prion protein (PrP) in PrP-deficient neuronal cell line Reviewed

    A Sakudo, DC Lee, K Saeki, Y Nakamura, K Inoue, Y Matsumoto, S Itohara, T Onodera

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   308 ( 3 )   660 - 667   2003.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Previous studies have reported a neuroprotective role for cellular prion protein (PrPC) against apoptosis induced by serum deprivation in an immortalized prion protein gene (Prnp)-deficient neuronal cell line, but the mechanisms remain unclear. In this study, to investigate the mechanisms by which PrPC prevents apoptosis, the authors compared apoptosis of Prnp(-/-) cells with that of Prnp(-/-) cells expressing the wild-type PrPC or PrPC lacking N-terminal octapeptide repeat region under serum-free conditions. Re-introduction of Prnp rescued cells from apoptosis, upregulated superoxide dismutase (SOD) activity, enhanced superoxide anion elimination, and inhibited caspase-3/9 activation. On the other hand, N-terminally truncated PrPC enhanced apoptosis accompanied by potentiation of superoxide production and caspase-3/9 activation due to inhibition of SOD. These results suggest that PrPC protects Prnp(-/-) cells from apoptosis via superoxide- and caspase-3/9-dependent pathways by upregulating SOD activity. Furthermore, the octapeptide repeat region of PrPC plays an essential role in regulating apoptosis and SOD activity. (C) 2003 Elsevier Inc. All rights reserved.

    DOI: 10.1016/S0006-29IX(03)01459-1

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  • Prions prevent brain damage after experimental brain injury: a preliminary report Reviewed

    S Hoshino, K Inoue, T Yokoyama, S Kobayashi, T Asakura, A Teramoto, S Itohara

    BRAIN EDEMA XII   86   297 - 299   2003

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    The physiological function of the normal cellular form of prion protein (PrPC) is not yet fully understood. In the current study we used prion protein gene knock-out mice (Prnp(-/-)) to assess the role of PrPC in traumatic brain injury. Prnp(+/-) and Prnp(-/-) mice were subjected to weight-drop contusional brain injury over the left parietal cortex. Prnp(-/-) mice manifested a significantly larger lesion volume and worse neuromotor scores than did their Prnp(+/-) litter-mates. IgG immunostaining revealed that in Prnp(-/-) mice the breakdown in the blood-brain barrier (BBB) was more extensive at 1 month after brain injury. Our results are in agreement with previous in vitro findings of the neuroprotective role of PrPC and further support the hypothesis that functional loss of PrPc plays a pathogenic role in prion diseases. We also suggest that PrPc modulates BBB function.

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  • In vivo glioma growth requires host-derived matrix metalloproteinase 2 for maintenance of angioarchitecture Reviewed

    M Takahashi, S Fukami, N Iwata, K Inoue, S Itohara, H Itoh, J Haraoka, TC Saido

    PHARMACOLOGICAL RESEARCH   46 ( 2 )   155 - 163   2002.8

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    Glioma, the most common form of brain tumor, has been shown mostly by in vitro studies to utilize matrix metalloproteinase (MMP) for invasive growth through degradation of the extracellular matrix. In order to examine the in vivo role of MMP, we established a rodent model of glioma progression using C6 rat glioma cells and analyzed the effect of tissue inhibitors of metalloproteinases (TIMPs). TIMP-2 rather than TIMP-1 caused significant reduction of the tumor size accompanied by the presence of degenerated blood vessels and ischemic necrosis. Because TIMP-2 inhibits MMP-2 preferentially, we then examined glioma growth in MMP-2-deficient mice and observed essentially identical consequences. While MMP-2 activity was present in the tumor and adjacent tissues of the wild-type mice, no MMP-2 activity was detected even in the tumor of the null mice, although C6 cells are known to express MMP-2. These observations suggest that glioma induces MMP-2 and utilizes its activity in the host tissue to support angiogenesis and to maintain angioarchitecture. (C) 2002 Elsevier Science Ltd. All rights reserved.

    DOI: 10.1016/S1043-6618(02)00081-6

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  • Expression of cellular prion-related protein by murine Langerhans cells and keratinocytes Reviewed

    M Sugaya, K Nakamura, T Watanabe, A Asahina, N Yasaka, YI Koyama, M Kusubata, Y Ushiki, K Kimura, A Morooka, S Irie, T Yokoyama, K Inoue, S Itohara, K Tamaki

    JOURNAL OF DERMATOLOGICAL SCIENCE   28 ( 2 )   126 - 134   2002.2

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    Transmissible spongiform encephalopathies are characterized by the accumulation of a proteinase-resistant isoform of the cellular prion-related protein (PrPe) within the central nervous system (CNS), The accumulation of scrapie-associated PrP (PrPSc) within cells of the lymphoreticular system prior to its accumulation in the CNS is regarded as important for the development of neurological diseases after peripheral inoculation. Little, however, is known as to which cells are the targets for peripheral inoculation. Here. the presence of PrPe on murine Langerhans cells (LC), dendritic cells in the skin and mucosa. and keratinocytes (KC) is demonstrated by immunohistochemical staining, Western-blotting and FACS analysis. The expression of PrPc mRNA in freshly purified LC and KC was also detected by reverse transcriptase-polymerase chain reaction. The expression of PrPc on LC was slightly increased during culture. These data suggest that LC and KC may be the targets for peripheral infection with prions. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

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  • Matrix metalloproteinase-2 in dentin matrix mineralization. Reviewed

    Satoyoshi M, Kawata A, Koizumi T, Inoue K, Itohara S, Teranaka T, Mikuni-Takagaki Y

    Journal of Endodontics.   27 ( 7 )   462 - 466   2001.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:LIPPINCOTT WILLIAMS & WILKINS  

    In the serum-free culture medium of bovine odontoblasts we detected active gelatinolytic metalloproteinases, matrix metalloproteinase (MMP)-2 and MMP-9 (gelatinases A and B). The activity of MMP-2, in particular, appeared suddenly around day 21 in the culture, coinciding with the development of odontoblastic cell processes and the loss of alkaline phosphatase. Reverse transcriptase-polymerase chain reaction analysis of these odontoblasts demonstrated that messages of MMP-2 but not MMP-9 increased significantly between day 15 and day 21. The in vitro observation indicates that medium conditioned by these odontoblasts and containing significant amounts of MMP-2 degrades not only the collagenous substrates but also purified dentin phosphophoryn as well. We have also observed that dephosphorylated dentin phosphoprotein becomes a better substrate for casein kinase II after limited proteolysis with MMP-2. These results support our working hypothesis that MMP-2-mediated proteolytic processing is an important step in accelerating the process of dentin matrix maturation, which includes phosphorylation and subsequent mineralization. As has been suggested previously, extracellular phosphorylation of matrix proteins is an important step in biomineralization both in bone and in dentin (Mikuni-Takagaki et al., J Bone Miner Res 1995;10:231-42; Zhu et al., Biochem J 1997; 323:637-43), Our present histochemical analysis in MMP-2 knockout mice confirms the concept with the delayed formation of mineralized tissues, dentin, and bone.

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MISC

  • マイトファジーとミトコンドリア病 Invited

    井上敬一、神吉智丈

    医学のあゆみ   281 ( 12 )   1145 - 1150   2022.6

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  • クリスパー転写活性化によるアルツハイマー病線維芽細胞モデルの作製 Invited

    井上敬一

    Clinical Neuroscience (臨床神経科学)   38 ( 8 )   1052 - 1054   2020.8

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  • ミトコンドリアオートファジーと老化との関連 Invited

    神吉智丈, 井上敬一

    FRAGRANCE JOURNAL   47 ( 8 )   36 - 39   2019.8

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  • オートファジーと疾患 Invited Reviewed

    神吉智丈, Kseniia Chernyshova, 井上敬一

    新潟医学会雑誌   133 ( 7・8 )   267 - 272   2019.8

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  • 哺乳類におけるミトコンドリアオートファジーの分子機構 Invited

    井上敬一, 山下俊一, 神吉智丈

    実験医学増刊   37 ( 12 )   58(1930) - 64(1936)   2019.7

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (other)  

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  • クリスパー遺伝子活性化によるアルツハイマー病細胞モデルの開発

    井上敬一

    神経科学ニュース   3   41 - 42   2018.7

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (other)  

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  • Osteocyte Functions and Bone Metabolism in MMP-2 Knockout Mouse

    The Bulletin of Kanagawa Dental College   35 ( 2 )   200 - 203   2007

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    Language:English   Publishing type:Rapid communication, short report, research note, etc. (bulletin of university, research institution)  

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  • 関節リウマチ オステオポンチン Invited

    野田政樹, 井上敬一, 近藤久貴, 湯本健司

    日本臨床増刊   63 ( 1 )   185 - 188   2005

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

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  • 骨・軟骨の器官形成と分化シグナル Invited

    野田政樹, 井上敬一, 近藤久貴, 及川薫, 中島和久

    実験医学増刊   23 ( 1 )   121 - 126   2005

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

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Presentations

  • CRISPR Transcriptional Activation Analysis Unmasks an Occult γ-Secretase Processivity Defect in Familial Alzheimer’s Disease Skin Fibroblasts.

    Keiichi Inoue, Oliveira LMA, Abeliovich A

    NEURO2019 第42回日本神経科学学会大会・第62回日本神経科学会大会  2019.7 

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    Event date: 2019.7

    Presentation type:Poster presentation  

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  • 哺乳類マイトファジーの生理機能と分子機構 Invited

    井上敬一

    自治医科大学 大学院特別講義  2022.11 

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    Presentation type:Public lecture, seminar, tutorial, course, or other speech  

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Industrial property rights

  • MMP-2遺伝子欠損モデル動物

    糸原重美, 井上敬一

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    Applicant:独立行政法人理化学研究所

    Application no:特願2003-324974  Date applied:2003.9

    Announcement no:特開2005-087095  Date announced:2005.4

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Works

  • Cover Image: Fibroblast model of Alzheimer's disease by CRISPR activation.

    Keiichi Inoue

    2021.9

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Awards

  • 令和4年度新潟大学優秀論文表彰

    2022   新潟大学  

    井上敬一

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  • 令和2年度新潟大学優秀論文表彰

    2020   新潟大学  

    井上 敬一

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  • Postdoctoral Fellowship

    2007   American Parkinson’s Disease Association  

    Inoue Keiichi

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:United States

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  • Druckenmiller Fellowship

    2007   New York Stem Cell Foundation (NYSCF)  

    Inoue Keiichi

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:United States

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Research Projects

  • マイトファジーによるミトコンドリア分解異常から見たアルツハイマー病の理解とその治療法の開発

    2023.4 - 2026.3

    公益財団法人小林財団  第11回研究助成 

    井上敬一

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    Authorship:Principal investigator 

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  • 温熱刺激はマイトファジーを誘導するのか?

    2022.5 - 2023.3

    日本健康開発財団  研究助成 

    井上敬一

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    Authorship:Principal investigator 

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  • レセプター依存的マイトファジーの誘導制御と生理機能の解明

    Grant number:22H02615  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    神吉智丈, 福田智行, 山下俊一, 井上敬一

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    Authorship:Coinvestigator(s) 

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  • マイトファジー制御による筋萎縮の遺伝子治療法の開発

    Grant number:20H04035  2020.4 - 2024.3

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    井上 敬一, 瀬原吉英

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    Authorship:Principal investigator 

    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

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  • 筋萎縮におけるマイトファジーの意義とその薬剤制御

    2020 - 2021

    花王健康科学研究会  助成金 

    井上敬一

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    Authorship:Principal investigator 

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  • RNA fociをターゲットにした人工的オートファジー誘導システムの構築

    2020.10 - 2022

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    井上 敬一

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    Authorship:Principal investigator 

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  • オートファジー活性化による結節性硬化症脳細胞病変の治療法開発

    2020 - 2021

    公益信託 康本徳守記念結節性硬化症関連神経難病研究基金 

    井上敬一

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    Authorship:Principal investigator 

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  • ミトコンドリアオートファジーは老化を制御するのか?

    Grant number:19K23822  2019.8 - 2021.3

    日本学術振興会  科学研究費助成事業 研究活動スタート支援  研究活動スタート支援

    井上 敬一

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    Authorship:Principal investigator 

    Grant amount:\2860000 ( Direct Cost: \2200000 、 Indirect Cost:\660000 )

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  • ミトコンドリアオートファジー:その孤発性パーキンソン病への関与

    2019 - 2022

    公益財団法人 武田科学振興財団  医学系研究助成 

    井上敬一

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    Authorship:Principal investigator  Grant type:Competitive

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  • マイトファジー不全仮説にもとづいたパーキンソン病モデル動物の作製

    2019 - 2020

    公益財団法人 鈴木謙三記念医科学応用研究財団  調査研究助成 

    井上敬一

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    Authorship:Principal investigator  Grant type:Competitive

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  • 第 36 回日本分子生物学会 海外ポスドク招聘企画

    2013.12

    日本分子生物学会  海外ポスドク招聘企画 

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  • レチノイドによるパーキンソン病抑止効果の検討

    2007 - 2008

    公益財団法人乙卯研究所  「レチノイドと脳神経疾患」研究助成 

    井上敬一

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    Authorship:Principal investigator  Grant type:Competitive

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  • 神経細胞における、オートファジー依存性細胞内タンパク質分解機構の機能解析

    2007

    公益財団法人 かなえ医薬振興財団  海外留学助成金 

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    Authorship:Principal investigator 

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  • 骨細胞ネットワークによる新規の骨石灰化メカニズムの解明

    2005

    文部科学省  科学研究費補助金(若手研究(B)) 

    井上敬一

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    Authorship:Principal investigator  Grant type:Competitive

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  • Matrix metalloproteinase-2による頭蓋骨成長制御メカニズムの解明

    2004.4 - 2005.3

    公益財団法人日本科学協会  笹川科学研究助成 

    井上敬一

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    Authorship:Principal investigator  Grant type:Competitive

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  • Molecular Bases for Bone Regeneration Research

    Grant number:14207056  2002 - 2005

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)  Grant-in-Aid for Scientific Research (A)

    NODA Masaki, NIFUJI Akira, TSUJI Kunikazu, INOUE Keiichi

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    Authorship:Coinvestigator(s) 

    Grant amount:\43160000 ( Direct Cost: \33200000 、 Indirect Cost:\9960000 )

    This research program has been aimed to understand the mechanisms for the bone formation and bone resumption to be contributing to contemplate measures for the regeneration of bone to treat the patients suffering from osteoporosis or the large bone defects. For this program we have main three purposes. The first one is to understand the mechanisms of osteoblastic differentiation. The second project purpose is to analyze the molecular cascade for differentiation of osteoclasts. The third research aim is to elucidate mechanisms underlying the cartilage destruction and bone destruction. The first purpose, we have revealed that CIZ is acting as antagonist against BMP actions. Furthermore, osteoblastic activity as well as osteoclastic activities are under the control of sympathetic nerves tone. These molecular regulations also lead to suppression of osteoblastic transcription factors such as Runx2. In addition, other molecules such as BMP antagonist, Sost as well as HLH proteins, have been shown to work together to modulate the function of osteoblasts.
    For the second purpose, we analyze the molecules which are contributing to osteoclast differentiation and have shown that osteopontin as well as Klotho proteins are involved in the regulation of osteoclastic activities, Klotho protein interacts with osteoprotegrins. Bone resorption results in osteopenia. However, at the same time suppression of bone formation by Tob which also is contributing to such reduction of bone mass during the differentiation of osteoblasts. MIT-F was identified to be involved in the regulation of osteoclastic differentiation.
    For the third purpose, we have shown that degradation of cartilage layers in the rehumatoidarthritis models could be mediated by OPN. We have also analyze the function of transcription factor, Sox9 and identified stem cells in tendons. These three research activities altogether contributed to understanding of bone and cartilage development and regeneration.

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Other research activities

  • 3rd grade Certified Specialist of Intellectual Property Management(administration)

    2020.1

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Teaching Experience (researchmap)

  • 大学院特別講義

    2022.11
    Institution name:自治医科大学大学院医学研究科

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Social Activities

  • 新潟大学オープンキャンパス 医学部医学科プログラム

    Role(s): Lecturer

    新潟大学医学部医学科  「最先端の研究に触れよう、若手研究者と交流しよう」  2021.8

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  • 令和元年度先端科学技術活用講座(高等学校)

    Role(s): Lecturer

    新潟県立教育センター  ⑷コース「オートファジーを見てみよう」  2019.6

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    Audience: Teachers

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Media Coverage

Academic Activities