2021/10/20 更新

写真a

カトウ タイスケ
加藤 泰介
KATO Taisuke
所属
脳研究所 生命科学リソース研究センター 准教授
職名
准教授
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学位

  • 博士(医学) ( 2010年3月   新潟大学 )

  • 修士(医科学) ( 2006年3月   新潟大学 )

  • 学士(農学) ( 2004年3月   新潟大学 )

研究キーワード

  • 包括脳ネットワーク

  • Small vessel disease

  • 遺伝性脳小血管病

  • 筋萎縮性側索硬化症

  • ゲノム編集

  • ポリグルタミン病

研究分野

  • ライフサイエンス / 神経科学一般

  • ライフサイエンス / 分子生物学

  • ライフサイエンス / 神経科学一般

経歴(researchmap)

  • 新潟大学   脳研究所   特任准教授

    2017年4月 - 現在

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  • 新潟大学   脳研究所   特任助教

    2013年10月 - 2016年3月

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経歴

  • 新潟大学   脳研究所 生命科学リソース研究センター   准教授

    2021年5月 - 現在

  • 新潟大学   脳研究所   特任准教授

    2017年4月 - 2021年4月

  • 新潟大学   脳研究所   特任助教

    2013年10月 - 2015年3月

  • 新潟大学   医歯学総合研究科   特任助教

    2010年5月 - 2011年3月

学歴

  • 新潟大学   大学院医歯学総合研究科   博士課程

    2006年4月 - 2010年3月

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  • 新潟大学   大学院医歯学総合研究科   修士課程

    2004年4月 - 2006年3月

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  • 新潟大学   農学部   応用生物化学科

    2000年4月 - 2004年3月

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所属学協会

 

論文

  • Hemorrhagic cerebral small vessel disease caused by a novel mutation in 3' UTR of collagen type IV alpha 1. 査読 国際誌

    Naoko Sakai, Masahiro Uemura, Taisuke Kato, Hiroaki Nozaki, Akihide Koyama, Shouichirou Ando, Hiroyuki Kamei, Motohiro Kato, Osamu Onodera

    Neurology. Genetics   6 ( 1 )   e383   2020年2月

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  • HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature. 査読 国際誌

    Masahiro Uemura, Hiroaki Nozaki, Taisuke Kato, Akihide Koyama, Naoko Sakai, Shoichiro Ando, Masato Kanazawa, Nozomi Hishikawa, Yoshinori Nishimoto, Kiran Polavarapu, Atchayaram Nalini, Akira Hanazono, Daisuke Kuzume, Akihiro Shindo, Mohammad El-Ghanem, Arata Abe, Aki Sato, Mari Yoshida, Takeshi Ikeuchi, Ikuko Mizuta, Toshiki Mizuno, Osamu Onodera

    Frontiers in neurology   11   545 - 545   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in high-temperature requirement A serine peptidase 1 (HTRA1). Recently, it was reported that several heterozygous mutations in HTRA1 also cause cerebral small vessel disease (CSVD). Although patients with heterozygous HTRA1-related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on HTRA1-related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous HTRA1-related CSVD has a milder clinical presentation of CARASIL. It seems that haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with HTRA1-related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.

    DOI: 10.3389/fneur.2020.00545

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  • Excessive Production of Transforming Growth Factor β1 Causes Mural Cell Depletion From Cerebral Small Vessels. 査読 国際誌

    Taisuke Kato, Yumi Sekine, Hiroaki Nozaki, Masahiro Uemura, Shoichiro Ando, Sachiko Hirokawa, Osamu Onodera

    Frontiers in aging neuroscience   12   151 - 151   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    It is increasingly becoming apparent that cerebrovascular dysfunction contributes to the pathogenic processes involved in vascular dementia, Alzheimer's disease, and other neurodegenerative disorders. Under these pathologic conditions, the degeneration of cerebral blood vessels is frequently accompanied by a loss of mural cells from the vascular walls. Vascular mural cells play pivotal roles in cerebrovascular functions, such as regulation of cerebral blood flow and maintenance of the blood-brain barrier (BBB). Therefore, cerebrovascular mural cell impairment is involved in the pathophysiology of vascular-related encephalopathies, and protecting these cells is essential for maintaining brain health. However, our understanding of the molecular mechanism underlying mural cell abnormalities is incomplete. Several reports have indicated that dysregulated transforming growth factor β (TGFβ) signaling is involved in the development of cerebral arteriopathies. These studies have specifically suggested the involvement of TGFβ overproduction. Although cerebrovascular toxicity via vascular fibrosis by extracellular matrix accumulation or amyloid deposition is known to occur with enhanced TGFβ production, whether increased TGFβ results in the degeneration of vascular mural cells in vivo remains unknown. Here, we demonstrated that chronic TGFβ1 overproduction causes a dropout of mural cells and reduces their coverage on cerebral vessels in both smooth muscle cells and pericytes. Mural cell degeneration was also accompanied by vascular luminal dilation. TGFβ1 overproduction in astrocytes significantly increased TGFβ1 content in the cerebrospinal fluid (CSF) and increased TGFβ signaling-regulated gene expression in both pial arteries and brain capillaries. These results indicate that TGFβ is an important effector that mediates mural cell abnormalities under pathological conditions related to cerebral arteriopathies.

    DOI: 10.3389/fnagi.2020.00151

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  • Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation. 査読 国際誌

    Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Takuya Konno, Tomohiko Ishihara, Osamu Onodera

    Neurobiology of disease   130   104534 - 104534   2019年10月

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    記述言語:英語  

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by accumulation of fragmented insoluble TDP-43 and loss of TDP-43 from the nucleus. Increased expression of exogenous TARDBP (encoding TDP-43) induces TDP-43 pathology and cytotoxicity, suggesting the involvement of aberrant expression of TDP-43 in the pathogenesis of ALS. In normal conditions, however, the amount of TDP-43 is tightly regulated by the autoregulatory mechanism involving alternative splicing of TARDBP mRNA. To investigate the influence of autoregulation dysfunction, we inhibited the splicing of cryptic intron 6 using antisense oligonucleotides in vivo. This inhibition doubled the Tardbp mRNA expression, increased the fragmented insoluble TDP-43, and reduced the number of motor neurons in the mouse spinal cord. In human induced pluripotent stem cell-derived neurons, the splicing inhibition of intron 6 increased TARDBP mRNA and decreased nuclear TDP-43. These non-genetically modified models exhibiting rise in the TARDBP mRNA levels suggest that TDP-43 autoregulation turbulence might be linked to the pathogenesis of ALS.

    DOI: 10.1016/j.nbd.2019.104534

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  • Ectopic expression induces abnormal somatodendritic distribution of tau in the mouse brain. 査読

    Kubo A, Ueda S, Yamane A, Wada-Kakuda S, Narita M, Matsuyama M, Nomori A, Takashima A, Kato T, Onodera O, Goto M, Ito M, Tomiyama T, Mori H, Murayama S, Ihara Y, Misonou H, Miyasaka T

    The Journal of neuroscience : the official journal of the Society for Neuroscience   2019年6月

  • Retinal Vasculopathy With Cerebral Leukodystrophy: Clinicopathologic Features of an Autopsied Patient With a Heterozygous TREX 1 Mutation. 査読 国際誌

    Rie Saito, Hiroaki Nozaki, Taisuke Kato, Yasuko Toyoshima, Hajime Tanaka, Yutaka Tsubata, Tetsuo Morioka, Yoh Horikawa, Kiyomitsu Oyanagi, Takashi Morita, Osamu Onodera, Akiyoshi Kakita

    Journal of neuropathology and experimental neurology   78 ( 2 )   181 - 186   2019年2月

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    記述言語:英語  

    Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an autosomal-dominant disorder involving the cerebral, retinal, renal, and other systemic microvessels due to frameshift mutations in the TREX1 gene. Under physiological conditions, the TREX1 protein is localized in the cellular cytoplasm and perinuclear area, but translocates into the nucleus in response to oxidative DNA damage. It has been speculated that aberrant localization of the protein may be associated with systemic microangiopathy in patients with RVCL. However, cellular expression of TREX1 in the brain and visceral organs of patients with RVCL has been unclear. Here, we report the clinicopathologic features of an autopsied patient with a heterozygous T249fs mutation in TREX1. The patient showed the clinical phenotype of vasculopathy with retinopathy, nephropathy, and stroke. CT with contrast enhancement demonstrated a tumorous lesion in the subcortical white matter. Histologically, the lesion consisted of confluent foci of necrosis with calcification and fibrous thickening of small vessel walls. TREX1 immunohistochemistry demonstrated positivity in the nuclei of cells in the CNS and visceral organs, indicating aberrant localization of the truncated protein, and the expression was remarkable in oligodendrocytes within the lesion, suggesting possible involvement of the protein in the pathomechanism of vasculopathy leading to white matter degeneration.

    DOI: 10.1093/jnen/nly115

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  • HTRA1 Mutations Identified in Symptomatic Carriers Have the Property of Interfering the Trimer-Dependent Activation Cascade. 査読 国際誌

    Masahiro Uemura, Hiroaki Nozaki, Akihide Koyama, Naoko Sakai, Shoichiro Ando, Masato Kanazawa, Taisuke Kato, Osamu Onodera

    Frontiers in neurology   10   693 - 693   2019年

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    記述言語:英語  

    Background: Mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Most carriers for HTRA1 mutations are asymptomatic, but more than 10 mutations have been reported in symptomatic carriers. The molecular differences between the mutations identified in symptomatic carriers and mutations identified only in CARASIL patients are unclear. HTRA1 is a serine protease that forms homotrimers, with each HTRA1 subunit activating the adjacent HTRA1 via the sensor domain of loop 3 (L3) and the activation domain of loop D (LD). Previously, we analyzed four HTRA1 mutant proteins identified in symptomatic carriers and found that they were unable to form trimers or had mutations in the LD or L3 domain. The mutant HTRA1s with these properties are presumed to inhibit trimer-dependent activation cascade. Indeed, these mutant HTRA1s inhibited wild-type (WT) protease activity. In this study, we further analyzed 15 missense HTRA1s to clarify the molecular character of mutant HTRA1s identified in symptomatic carriers. Methods: We analyzed 12 missense HTRA1s identified in symptomatic carriers (hetero-HTRA1) and three missense HTRA1s found only in CARASIL (CARASIL-HTRA1). The protease activity of the purified recombinant mutant HTRA1s was measured using fluorescein isothiocyanate-labeled casein as substrate. Oligomeric structure was evaluated by size-exclusion chromatography. The protease activities of mixtures of WT with each mutant HTRA1 were also measured. Results: Five hetero-HTRA1s had normal protease activity and were excluded from further analysis. Four of the seven hetero-HTRA1s and one of the three CARASIL-HTRA1s were unable to form trimers. The other three hetero-HTRA1s had mutations in the LD domain. Together with our previous work, 10 of 11 hetero-HTRA1s and two of six CARASIL-HTRA1s were either defective in trimerization or had mutations in the LD or L3 domain (P = 0.006). By contrast, eight of 11 hetero-HTRA1s and two of six CARASIL-HTRA1 inhibited WT protease activity (P = 0.162). Conclusions: HTRA1 mutations identified in symptomatic carriers have the property of interfering the trimer-dependent activation cascade of HTRA1.

    DOI: 10.3389/fneur.2019.00693

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  • CADM1 is a diagnostic marker in early-stage mycosis fungoides: Multicenter study of 58 cases. 査読

    Yuki A, Shinkuma S, Hayashi R, Fujikawa H, Kato T, Homma E, Hamade Y, Onodera O, Matsuoka M, Shimizu H, Iwata H, Abe R

    Journal of the American Academy of Dermatology   79 ( 6 )   1039 - 1046   2018年12月

  • Robustness and Vulnerability of the Autoregulatory System That Maintains Nuclear TDP-43 Levels: A Trade-off Hypothesis for ALS Pathology Based on in Silico Data. 査読 国際誌

    Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Sou Kasahara, Takuya Konno, Tomohiko Ishihara, Osamu Onodera

    Frontiers in neuroscience   12   28 - 28   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay. The level of nuclear TDP-43 is tightly regulated by these mechanisms, which control the amount of mRNA that may be translated. Based on the results of previous experiments, we developed an in silico model that mimics the intracellular dynamics of TDP-43 and examined TDP-43 metabolism under various conditions. We discovered an inherent trade-off in this mechanism between transcriptional redundancy, which maintains the robustness of TDP-43 metabolism, and vulnerability to specific interfering factors. These factors include an increased tendency of TDP-43 to aggregate, impaired nuclear-cytoplasmic TDP-43 transport, and a decreased efficiency of degrading abnormal proteins, all of which are functional abnormalities related to the gene that causes familial ALS/FTD. When these conditions continue at a certain intensity, the vulnerability of the autoregulatory machinery becomes apparent over time, and transcriptional redundancy enters a vicious cycle that ultimately results in TDP-43 pathology. The results obtained using this in silico model reveal the difference in TDP-43 metabolism between normal and disease states. Furthermore, using this model, we simulated the effect of a decrease in TDP-43 transcription and found that this decrease improved TDP-43 pathology and suppressed the abnormal propagation of TDP-43. Therefore, we propose a potential therapeutic strategy to suppress transcriptional redundancy, which is the driving force of the pathological condition caused by the specific factors described above, in patients with ALS presenting with TDP-43 pathology. An ALS animal model exhibiting TDP-43 pathology without overexpression of exogenous TDP-43 should be developed to investigate the effect of alleviating the transcriptional redundancy of TARDBP.

    DOI: 10.3389/fnins.2018.00028

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  • Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43 査読

    Akihide Koyama, Akihiro Sugai, Taisuke Kato, Tomohiko Ishihara, Atsushi Shiga, Yasuko Toyoshima, Misaki Koyama, Takuya Konno, Sachiko Hirokawa, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera

    NUCLEIC ACIDS RESEARCH   44 ( 12 )   5820 - 5836   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons-especially neurons with mislocalized TDP-43-the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS.

    DOI: 10.1093/nar/gkw499

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  • Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: Evidence for clinico-pathologic subtypes 査読

    Ryoko Takeuchi, Mari Tada, Atsushi Shiga, Yasuko Toyoshima, Takuya Konno, Tomoe Sato, Hiroaki Nozaki, Taisuke Kato, Masao Horie, Hiroshi Shimizu, Hirohide Takebayashi, Osamu Onodera, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi

    ACTA NEUROPATHOLOGICA COMMUNICATIONS   4 ( 1 )   61   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are types of major TDP-43 (43-kDa TAR DNA-binding protein) proteinopathy. Cortical TDP-43 pathology has been analyzed in detail in cases of FTLD-TDP, but is still unclear in cases of ALS. We attempted to clarify the cortical and subcortical TDP-43 pathology in Japanese cases of sporadic ALS (n = 96) using an antibody specific to phosphorylated TDP-43 (pTDP-43). The cases were divided into two groups: those without pTDP-43-positive neuronal cytoplasmic inclusions in the hippocampal dentate granule cells (Type 1, n = 63), and those with such inclusions (Type 2, n = 33). Furthermore, the Type 2 cases were divided into two subgroups based on semi-quantitative estimation of pTDP-43-positive dystrophic neurites (DNs) in the temporal neocortex: Type 2a (accompanied by no or few DNs, n = 22) and Type 2b (accompanied by abundant DNs, n = 11). Clinico-pathologic analysis revealed that cognitive impairment was a feature in patients with Type 2a and Type 2b, but not in those with Type 1, and that importantly, Type 2b is a distinct subtype characterized by a poor prognosis despite the less severe loss of lower motor neurons, the unusual subcortical dendrospinal pTDP-43 pathology, and more prominent glial involvement in cortical pTDP-43 pathology than other two groups. Considering the patient survival time and severity of motor neuron loss in each group, transition from Type 1 to Type 2, or from Type 2a to Type 2b during the disease course appeared unlikely. Therefore, each of these three groups was regarded as an independent subtype.

    DOI: 10.1186/s40478-016-0335-2

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  • Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL. 査読

    Nozaki H, Kato T, Nihonmatsu M, Saito Y, Mizuta I, Noda T, Koike R, Miyazaki K, Kaito M, Ito S, Makino M, Koyama A, Shiga A, Uemura M, Sekine Y, Murakami A, Moritani S, Hara K, Yokoseki A, Kuwano R, Endo N, Momotsu T, Yoshida M, Nishizawa M, Mizuno T, Onodera O

    Neurology   86 ( 21 )   1964 - 74   2016年5月

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  • Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801 査読

    Kato T, Abe Y, Hirokawa S, Iwakura Y, Mizuno M, Namba H, Nawa H

    CURRENT MOLECULAR MEDICINE   15 ( 3 )   222 - 236   2015年

  • Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis 査読

    Tomohiko Ishihara, Yuko Ariizumi, Atsushi Shiga, Taisuke Kato, Chun-Feng Tan, Tatsuya Sato, Yukari Miki, Mariko Yokoo, Takeshi Fujino, Akihide Koyama, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera

    HUMAN MOLECULAR GENETICS   22 ( 20 )   4136 - 4147   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Disappearance of TAR-DNA-binding protein 43 kDa (TDP-43) from the nucleus contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS), but the nuclear function of TDP-43 is not yet fully understood. TDP-43 associates with nuclear bodies including Gemini of coiled bodies (GEMs). GEMs contribute to the biogenesis of uridine-rich small nuclear RNA (U snRNA), a component of splicing machinery. The number of GEMs and a subset of U snRNAs decrease in spinal muscular atrophy, a lower motor neuron disease, suggesting that alteration of U snRNAs may also underlie the molecular pathogenesis of ALS. Here, we investigated the number of GEMs and U11/12-type small nuclear ribonucleoproteins (snRNP) by immunohistochemistry and the level of U snRNAs using real-time quantitative RT-PCR in ALS tissues. GEMs decreased in both TDP-43-depleted HeLa cells and spinal motor neurons in ALS patients. Levels of several U snRNAs decreased in TDP-43-depleted SH-SY5Y and U87-MG cells. The level of U12 snRNA was decreased in tissues affected by ALS (spinal cord, motor cortex and thalamus) but not in tissues unaffected by ALS (cerebellum, kidney and muscle). Immunohistochemical analysis revealed the decrease in U11/12-type snRNP in spinal motor neurons of ALS patients. These findings suggest that loss of TDP-43 function decreases the number of GEMs, which is followed by a disturbance of pre-mRNA splicing by the U11/U12 spliceosome in tissues affected by ALS.

    DOI: 10.1093/hmg/ddt262

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  • Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia (vol 16, pg 307-320, 2011) 査読

    Kato T, Abe Y, Sotoyama H, Kakita A, Kominami R, Hirokawa S, Ozaki M, Takahashi H, Nawa H

    MOLECULAR PSYCHIATRY   18 ( 8 )   951   2013年8月

  • Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72 査読

    Takuya Konno, Atsushi Shiga, Akira Tsujino, Akihiro Sugai, Taisuke Kato, Kazuaki Kanai, Akio Yokoseki, Hiroto Eguchi, Satoshi Kuwabara, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

    Journal of Neurology, Neurosurgery and Psychiatry   84 ( 4 )   398 - 401   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ Publishing Group  

    Background A GGGGCC hexanucleotide repeat expansion in C9ORF72 occurs on a chromosome 9p21 locus that is linked with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in white populations. The diseases resulting from this expansion are referred to as 'c9FTD/ALS'. It has been suggested that c9FTD/ALS arose from a single founder. However, the existence of c9FTD/ALS in non-white populations has not been evaluated. Results We found two index familial ALS (FALS) patients with c9FTD/ALS in the Japanese population. The frequency of c9FTD/ALS was 3.4% (2/58 cases) in FALS. No patients with sporadic ALS (n=110) or control individuals (n=180) had the expansion. Neuropathological findings of an autopsy case were indistinguishable from those of white patients. Although the frequency of risk alleles identified in white subjects is low in Japanese, one patient had all 20 risk alleles and the other had all but one. The estimated haplotype indicated that the repeat expansion in these patients was located on the chromosome with the risk haplotype identified in white subjects. Conclusions C9ORF72 repeat expansions were present in a Japanese cohort of ALS patients, but they were rare. Intriguingly, Japanese patients appear to carry the same risk haplotype identified in white populations.

    DOI: 10.1136/jnnp-2012-302272

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  • Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS 査読

    Atsushi Shiga, Tomohiko Ishihara, Akinori Miyashita, Misaki Kuwabara, Taisuke Kato, Norihiro Watanabe, Akie Yamahira, Chigusa Kondo, Akio Yokoseki, Masuhiro Takahashi, Ryozo Kuwano, Akiyoshi Kakita, Masatoyo Nishizawa, Hitoshi Takahashi, Osamu Onodera

    PLOS ONE   7 ( 8 )   e43120   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and POLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.

    DOI: 10.1371/journal.pone.0043120

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  • [CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) and CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)]. 査読

    Kato T, Nishizawa M, Onodera M

    Nihon rinsho. Japanese journal of clinical medicine   69 Suppl 10   320 - 324   2011年12月

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    出版者・発行元:Pt 2  

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  • Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-β1 via cleavage of proTGF-β1. 査読

    Shiga A, Nozaki H, Yokoseki A, Nihonmatsu M, Kawata H, Kato T, Koyama A, Arima K, Ikeda M, Katada S, Toyoshima Y, Takahashi H, Tanaka A, Nakano I, Ikeuchi T, Nishizawa M, Onodera O

    Human molecular genetics   20 ( 9 )   1800 - 1810   2011年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:9  

    DOI: 10.1093/hmg/ddr063

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  • Neuregulin-1 signals from the periphery regulate AMPA receptor sensitivity and expression in GABAergic interneurons in developing neocortex. 査読

    Abe Yuichi, Namba Hisaaki, Kato Taisuke, Iwakura Yuriko, Nawa Hiroyuki

    J Neurosci   31 ( 15 )   5699 - 5709   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuregulin-1 (NRG1) signaling is thought to contribute to both neuronal development and schizophrenia neuropathology. Here, we describe the developmental effects of excessive peripheral NRG1 signals on synaptic activity and AMPA receptor expression of GABAergic interneurons in postnatal rodent neocortex. A core peptide common to all NRG1 variants (eNRG1) was subcutaneously administered to mouse pups. Injected eNRG1 penetrated the blood-brain barrier and activated ErbB4 NRG1 receptors in the neocortex, in which ErbB4 mRNA is predominantly expressed by parvalbumin-positive GABAergic interneurons. We prepared neocortical slices from juvenile mice that were receiving eNRG1 subchronically and recorded inhibitory synaptic activity from layer V pyramidal neurons. Postnatal eNRG1 treatment significantly enhanced polysynaptic IPSCs, although monosynaptic IPSCs were not affected. Examination of excitatory inputs to parvalbumin-containing GABAergic interneurons revealed that eNRG1 treatment significantly increased AMPA-triggered inward currents and the amplitudes and frequencies of miniature EPSCs (mEPSCs). Similar effects on mEPSCs were observed in mice treated with a soluble, full-length

    DOI: 10.1523/JNEUROSCI.3477-10.2011

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  • Neuregulin-1 Signals from the Periphery Regulate AMPA Receptor Sensitivity and Expression in GABAergic Interneurons in Developing Neocortex 査読

    Yuichi Abe, Hisaaki Namba, Taisuke Kato, Yuriko Iwakura, Hiroyuki Nawa

    JOURNAL OF NEUROSCIENCE   31 ( 15 )   5699 - 5709   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOC NEUROSCIENCE  

    Neuregulin-1 (NRG1) signaling is thought to contribute to both neuronal development and schizophrenia neuropathology. Here, we describe the developmental effects of excessive peripheral NRG1 signals on synaptic activity and AMPA receptor expression of GABAergic interneurons in postnatal rodent neocortex. A core peptide common to all NRG1 variants (eNRG1) was subcutaneously administered to mouse pups. Injected eNRG1 penetrated the blood-brain barrier and activated ErbB4 NRG1 receptors in the neocortex, in which ErbB4 mRNA is predominantly expressed by parvalbumin-positive GABAergic interneurons. We prepared neocortical slices from juvenile mice that were receiving eNRG1 subchronically and recorded inhibitory synaptic activity from layer V pyramidal neurons. Postnatal eNRG1 treatment significantly enhanced polysynaptic IPSCs, although monosynaptic IPSCs were not affected. Examination of excitatory inputs to parvalbumin-containing GABAergic interneurons revealed that eNRG1 treatment significantly increased AMPA-triggered inward currents and the amplitudes and frequencies of miniature EPSCs (mEPSCs). Similar effects on mEPSCs were observed in mice treated with a soluble, full-length form of NRG1 type I. Consistent with the electrophysiologic data, expression of the AMPA receptor GluA1 (i.e., GluR1, GluRA) was upregulated in the postsynaptic density/cytoskeletal fraction prepared from eNRG1-treated mouse neocortices. Cortical GABAergic neurons cultured with eNRG1 exhibited a significant increase in surface GluA1 immunoreactivity at putative synaptic sites on their dendrites. These results indicate that NRG1 circulating in the periphery influences postnatal development of synaptic AMPA receptor expression in cortical GABAergic interneurons and may play a role in conditions characterized by GABA-associated neuropathologic processes.

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  • Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia 査読

    T. Kato, Y. Abe, H. Sotoyama, A. Kakita, R. Kominami, S. Hirokawa, M. Ozaki, H. Takahashi, H. Nawa

    MOLECULAR PSYCHIATRY   16 ( 3 )   307 - 320   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Neuregulin-1 (NRG1) is implicated in the etiology or pathology of schizophrenia, although its biological roles in this illness are not fully understood. Human midbrain dopaminergic neurons highly express NRG1 receptors (ErbB4). To test its neuropathological role in the neurodevelopmental hypothesis of schizophrenia, we administered type-1 NRG1 protein to neonatal mice and evaluated the immediate and subsequent effects on dopaminergic neurons and their associated behaviors. Peripheral NRG1 administration activated midbrain ErbB4 and elevated the expression, phosphorylation and enzyme activity of tyrosine hydroxylase (TH), which ultimately increased dopamine levels. The hyperdopaminergic state was sustained in the medial prefrontal cortex after puberty. There were marked increases in dopaminergic terminals and TH levels. In agreement, higher amounts of dopamine were released from this brain region of NRG1-treated mice following high potassium stimulation. Furthermore, NRG1-treated mice exhibited behavioral impairments in prepulse inhibition, latent inhibition, social behaviors and hypersensitivity to methamphetamine. However, there were no gross abnormalities in brain structures or other phenotypic features of neurons and glial cells. Collectively, our findings provide novel insights into neurotrophic contribution of NRG1 to dopaminergic maldevelopment and schizophrenia pathogenesis. Molecular Psychiatry (2011) 16, 307-320; doi:10.1038/mp.2010.10; published online 9 February 2010

    DOI: 10.1038/mp.2010.10

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  • Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia. 査読

    Kato T, Abe Y, Sotoyama H, Kakita A, Kominami R, Hirokawa S, Ozaki M, Takahashi H, Nawa H

    Mol Psychiatry   16 ( 3 )   307 - 320   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuregulin-1 (NRG1) is implicated in the etiology or pathology of schizophrenia, although its biological roles in this illness are not fully understood. Human midbrain dopaminergic neurons highly express NRG1 receptors (ErbB4). To test its neuropathological role in the neurodevelopmental hypothesis of schizophrenia, we administered type-1 NRG1 protein to neonatal mice and evaluated the immediate and subsequent effects on dopaminergic neurons and their associated behaviors. Peripheral NRG1 administration activated midbrain ErbB4 and elevated the expression, phosphorylation and enzyme activity of tyrosine hydroxylase (TH), which ultimately increased dopamine levels. The hyperdopaminergic state was sustained in the medial prefrontal cortex after puberty. There were marked increases in dopaminergic terminals and TH levels. In agreement, higher amounts of dopamine were released from this brain region of NRG1-treated mice following high potassium stimulation. Furthermore, NRG1-treated mice exhibited behavioral impairments in prepulse inhibition, latent inhibition, social behaviors and hypersensitivity to methamphetamine. However, there were no gross abnormalities in brain structures o

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  • Phenotypic Characterization of Transgenic Mice Overexpressing Neuregulin-1 査読

    Taisuke Kato, Atsushi Kasai, Makoto Mizuno, Liang Fengyi, Norihito Shintani, Sadaaki Maeda, Minesuke Yokoyama, Miwako Ozaki, Hiroyuki Nawa

    PLOS ONE   5 ( 12 )   e14185   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Background: Neuregulin-1 (NRG1) is one of the susceptibility genes for schizophrenia and implicated in the neurotrophic regulation of GABAergic and dopaminergic neurons, myelination, and NMDA receptor function. Postmortem studies often indicate a pathologic association of increased NRG1 expression or signaling with this illness. However, the psychobehavioral implication of NRG1 signaling has mainly been investigated using hypomorphic mutant mice for individual NRG1 splice variants.
    Methodology/Principal Findings: To assess the behavioral impact of hyper NRG1 signaling, we generated and analyzed two independent mouse transgenic (Tg) lines carrying the transgene of green fluorescent protein (GFP)-tagged type-1 NRG1 cDNA. The promoter of elongation-factor 1 alpha gene drove ubiquitous expression of GFP-tagged NRG1 in the whole brain. As compared to control littermates, both heterozygous NRG1-Tg lines showed increased locomotor activity, a nonsignificant trend toward decreasing prepulse inhibition, and decreased context-dependent fear learning but exhibited normal levels of tone-dependent learning. In addition, social interaction scores in both Tg lines were reduced in an isolation-induced resident-intruder test. There were also phenotypic increases in a GABAergic marker (parvalbumin) as well as in myelination markers (myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase) in their frontal cortex, indicating the authenticity of NRG1 hyper-signaling, although there were marked decreases in tyrosine hydroxylase levels and dopamine content in the hippocampus.
    Conclusions: These findings suggest that aberrant hyper-signals of NRG1 also disrupt various cognitive and behavioral processes. Thus, neuropathological implication of hyper NRG1 signaling in psychiatric diseases should be evaluated with further experimentation.

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  • Antipsychotic Potential of Quinazoline ErbB1 Inhibitors in a Schizophrenia Model Established With Neonatal Hippocampal Lesioning 査読

    Makoto Mizuno, Yuriko Iwakura, Masako Shibuya, Yingjun Zheng, Takeyoshi Eda, Taisuke Kato, Yohei Takasu, Hiroyuki Nawa

    JOURNAL OF PHARMACOLOGICAL SCIENCES   114 ( 3 )   320 - 331   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

    Hyper-signaling of the epidermal growth factor receptor family (ErbB) is implicated in the pathophysiology of schizophrenia. Various quinazoline inhibitors targeting ErbB1 or ErbB2 - 4 have been developed as anti-cancer agents and might be useful for antipsychotic treatment. In the present study, we used an animal model of schizophrenia established by neonatal hippocampal lesioning and evaluated the neurobehavioral consequences of ErbB1-inhibitor treatment. Subchronic administration of the ErbB1 inhibitor ZD1839 to the cerebroventricle of rats receiving neonatal hippocampal lesioning ameliorated deficits in prepulse inhibition as well as those in the latent inhibition of tone-dependent fear learning. There were no apparent adverse effects on basal learning scores or locomotor activity, however. The administration of other ErbB1 inhibitors, PD153035 and OSI-774, similarly attenuated the prepulse inhibition impairment of this animal model. In parallel, there were decreases in ErbB1 phosphorylation in animals treated with ErbB1 inhibitors. These results indicate an antipsychotic potential of quinazoline ErbB1 inhibitors. ErbB receptor tyrosine kinases may be novel therapeutic targets for schizophrenia or its related psychotic symptoms.

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  • Measurement and comparison of serum neuregulin 1 immunoreactivity in control subjects and patients with schizophrenia: an influence of its genetic polymorphism 査読

    M. Shibuya, E. Komi, R. Wang, T. Kato, Y. Watanabe, M. Sakai, M. Ozaki, T. Someya, H. Nawa

    JOURNAL OF NEURAL TRANSMISSION   117 ( 7 )   887 - 895   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER WIEN  

    Neuregulin-1 (NRG1) gene is implicated in the etiology or neuropathology of schizophrenia, although its biological contribution to this illness is not fully understood. We have established an enzyme-linked immunosorbent assay (ELISA), which recognizes the NRG1 beta 1 immunoglobulin-like (Ig) domain, and measured soluble Ig-NRG1 immunoreactivity in the sera of chronic schizophrenia patients (n = 40) and healthy volunteers (n = 59). ELISA detected remarkably high concentrations of Ig-NRG1 immunoreactivity in human serum (mean 5.97 +/- A 0.40 ng/mL, similar to 213 +/- A 14 pM). Gender and diagnosis exhibited significant effects on serum Ig-NRG1 immunoreactivity. Mean Ig-NRG1 immunoreactivity in the schizophrenia group was 63.2% of that measured in the control group. Ig-NRG1 immunoreactivity in women was 147.1% of that seen in men. We also attempted to correlate six SNPs of NRG1 genome with serum Ig-NRG1 immunoreactivity. Analysis of covariance with compensation for gender identified a significant interaction between diagnosis and SNP8NRG243177 allele. The T allele of this SNP significantly contributed to the disease-associated decrease in Ig-NRG1 immunoreactivity. Although we hypothesized a chronic influence of antipsychotic medications, there was no significant effect of chronic haloperidol treatment on serum Ig-NRG1 immunoreactivity in monkeys. These findings suggest that serum NRG1 levels are decreased in patients with chronic schizophrenia and influenced by their SNP8NRG243177 alleles.

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  • Measurement and comparison of serum neuregulin 1 immunoreactivity in control subjects and patients with schizophrenia: an influence of its genetic polymorphism. 査読

    Shibuya M, Komi E, Wang R, Kato T, Watanabe Y, Sakai M, Ozaki M, Someya T, Nawa H

    J Neural Transm   117 ( 7 )   887 - 895   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuregulin-1 (NRG1) gene is implicated in the etiology or neuropathology of schizophrenia, although its biological contribution to this illness is not fully understood. We have established an enzyme-linked immunosorbent assay (ELISA), which recognizes the NRG1beta1 immunoglobulin-like (Ig) domain, and measured soluble Ig-NRG1 immunoreactivity in the sera of chronic schizophrenia patients (n = 40) and healthy volunteers (n = 59). ELISA detected remarkably high concentrations of Ig-NRG1 immunoreactivity in human serum (mean 5.97 +/- 0.40 ng/mL, ~213 +/- 14 pM). Gender and diagnosis exhibited significant effects on serum Ig-NRG1 immunoreactivity. Mean Ig-NRG1 immunoreactivity in the schizophrenia group was 63.2% of that measured in the control group. Ig-NRG1 immunoreactivity in women was 147.1% of that seen in men. We also attempted to correlate six SNPs of NRG1 genome with serum Ig-NRG1 immunoreactivity. Analysis of covariance with compensation for gender identified a significant interaction between diagnosis and SNP8NRG243177 allele. The T allele of this SNP significantly contributed to the disease-associated decrease in Ig-NRG1 immunoreactivity. Although we hypothesized a chronic

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  • Distinct ErbB receptor binding and signaling of neuregulin-1 splicing isoforms 査読

    Wang Ran, Iwakura Yuriko, Takei Nobuyuki, Ishizuka Yuta, Zheng Yingjun, Kato Taisuke, Higashiyama Shigeki, Nawa Hiroyuki

    NEUROSCIENCE RESEARCH   68   E142   2010年

  • Molecular pathology of ErbB signaling in schizophrenia and its models 査読

    Nawa Hiroyuki, Mizuno Makoto, Sotoyama Hidekazu, Zheng Yingjun, Kato Taisuke, Abe Yuichi, Sakai Miwako, Shibuya Masako, Eda Takeyoshi, Wang Ran, Araki Kazuaki, Ishizuka Yuta, Takei Nobuyuki, Iwakura Yuriko, Namba Hisaaki

    NEUROSCIENCE RESEARCH   65   S31   2009年

  • Neonatal exposure to neuregulin-1 results in distinct behavioral abnormalities in mice; Comparison with other cytokine treatments 査読

    Nawa H, Kato T, Abe Y, Mizuno M, Araki K, Takei N, Ozaki M

    SCHIZOPHRENIA BULLETIN   33 ( 2 )   320   2007年3月

  • In vivo action of ErbB ligands on synaptic development and neurobehavioral consequences: implications in schizophrenia 査読

    Nawa H, Kato T, Tsuda N, Mizuno M, Takei N, Ozaki M, Yokomaku D

    JOURNAL OF NEUROCHEMISTRY   98   80   2006年7月

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MISC

  • Type IV collagen α1の3'UTRの新規変異による脳小血管病

    酒井 直子, 上村 昌寛, 加藤 泰介, 安藤 昭一朗, 野崎 洋明, 亀井 博之, 加藤 元博, 小野寺 理

    臨床神経学   59 ( Suppl. )   S327 - S327   2019年11月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 歯状核赤核・淡蒼球ルイ体萎縮症モデルマウスに対するゲノム編集効果

    小池 佑佳, 加藤 泰介, 廣川 祥子, 小林 憲太, 辻 省次, 小野寺 理

    神経治療学   36 ( 6 )   S218 - S218   2019年10月

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    記述言語:日本語   出版者・発行元:(一社)日本神経治療学会  

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  • Therapeutic strategy based on genome editing for dentatorubral-pallidoluysian atrophy(和訳中)

    Koike Yuka, 加藤 泰介, 廣川 祥子, 小林 憲太, 辻 省次, 小野寺 理

    てんかん研究   37 ( 2 )   549 - 549   2019年9月

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    記述言語:英語   出版者・発行元:(一社)日本てんかん学会  

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  • 家族性脳小血管病患者で報告された変異型HTRA1蛋白質の機能解析

    上村 昌寛, 野崎 洋明, 加藤 泰介, 小山 哲秀, 小野寺 理

    生命科学系学会合同年次大会   2017年度   [1P - 1241]   2017年12月

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    記述言語:英語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • 血管性認知症の再定義(Serine protease HTRA1 deficiency induces arteriopathy in cerebral small vessels)

    加藤 泰介, 関根 有美, 藤田 菜摘, 野崎 洋明, 廣川 祥子, 佐藤 俊哉, 辻 省次, 小野寺 理

    生命科学系学会合同年次大会   2017年度   [1PW21 - 5]   2017年12月

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  • 家族性脳小血管病患者で報告された変異型HTRA1蛋白質の機能解析

    上村 昌寛, 野崎 洋明, 加藤 泰介, 小山 哲秀, 小野寺 理

    生命科学系学会合同年次大会   2017年度   [1P - 1241]   2017年12月

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    記述言語:英語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • 血管性認知症の再定義 脳の小血管におけるセリンプロテアーゼHTRA1欠損は動脈症を誘発する(Serine protease HTRA1 deficiency induces arteriopathy in cerebral small vessels)

    加藤 泰介, 関根 有美, 藤田 菜摘, 野崎 洋明, 廣川 祥子, 佐藤 俊哉, 辻 省次, 小野寺 理

    生命科学系学会合同年次大会   2017年度   [1PW21 - 5]   2017年12月

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    記述言語:英語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • RVCL関連変異の細胞内局在についての検討

    笠原 杏子, 加藤 泰介, 野崎 洋明, 小山 哲秀, 小野寺 理

    Dementia Japan   31 ( 4 )   572 - 572   2017年10月

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    記述言語:日本語   出版者・発行元:(一社)日本認知症学会  

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  • CARASILでのヘテロ接合体におけるHTRA1変異の異なる発症機序(Distinct mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL)

    野崎 洋明, 加藤 泰介, 水田 依久子, 水野 敏樹, 西澤 正豊, 小野寺 理

    日本内科学会雑誌   106 ( Suppl. )   184 - 184   2017年2月

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    記述言語:英語   出版者・発行元:(一社)日本内科学会  

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  • Distinct mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL(和訳中)

    野崎 洋明, 加藤 泰介, 水田 依久子, 野田 智子, 宮崎 一秀, 吉田 眞理, 西澤 正豊, 水野 敏樹, 小野寺 理

    Dementia Japan   30 ( 4 )   533 - 533   2016年10月

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  • ヘテロ接合体でCARASILを呈するHTRA1変異の特有の機序(Distinct mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL)

    野崎 洋明, 加藤 泰介, 水田 依久子, 野田 智子, 宮崎 一秀, 吉田 眞理, 西澤 正豊, 水野 敏樹, 小野寺 理

    Dementia Japan   30 ( 4 )   533 - 533   2016年10月

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  • 核内TDP-43減少は細胞質内TDP-43 mRNA増加をもたらす

    須貝 章弘, 小山 哲秀, 加藤 泰介, 今野 卓哉, 石原 智彦, 西澤 正豊, 小野寺 理

    臨床神経学   54 ( Suppl. )   S62 - S62   2014年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • ALS関連TARDBP遺伝子変異は自身の選択的スプライシングに影響をおよぼすか?

    今野 卓哉, 小山 哲秀, 逸見 文昭, 小山 美咲, 須貝 章弘, 加藤 泰介, 石原 智彦, 西澤 正豊, 小野寺 理

    臨床神経学   54 ( Suppl. )   S200 - S200   2014年12月

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  • TGFβ1過剰発現マウスは脳小血管壁細胞の異常をきたす

    関根 有美, 加藤 泰介, 野崎 洋明, 廣川 祥子, 佐藤 俊哉, 志賀 篤, 笹岡 敏邦, 西澤 正豊, 小野寺 理

    臨床神経学   54 ( Suppl. )   S5 - S5   2014年12月

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  • HTRA1変異ヘテロ接合者における脳小血管病の発症機序

    野崎 洋明, 加藤 泰介, 齊藤 洋兵, 小山 哲秀, 西澤 正豊, 小野寺 理

    Dementia Japan   28 ( 4 )   475 - 475   2014年10月

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  • 周皮細胞被覆率の解析による脳小血管障害評価法の検討

    関根 有美, 加藤 泰介, 野崎 洋明, 廣川 祥子, 佐藤 俊哉, 志賀 篤, 横山 峯介, 西澤 正豊, 小野寺 理

    臨床神経学   53 ( 12 )   1477 - 1477   2013年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • TDP-43量はTDP-43に惹起される自己mRNAのスプライシングで制御される

    須貝 章弘, 小山 哲秀, 今野 卓哉, 加藤 泰介, 西澤 正豊, 小野寺 理

    臨床神経学   53 ( 12 )   1411 - 1411   2013年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • Dominant negative効果をもつ変異型HTRA1はヘテロ接合体でも脳小血管病を引き起こす

    野崎 洋明, 斉藤 洋平, 二本松 萌, 小山 哲秀, 加藤 泰介, 西澤 正豊, 小野寺 理

    臨床神経学   53 ( 12 )   1540 - 1540   2013年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 片側アリルにのみHTRA1ミスセンス変異を有する例でも脳小血管病を引き起こす

    野崎 洋明, 二本松 萌, 斎藤 洋兵, 針生 真弥, 水野 敏樹, 水田 依久子, 志賀 篤, 小山 哲秀, 加藤 泰介, 野田 智子, 垣内 無一, 伊藤 彰一, 西澤 正豊, 小野寺 理

    臨床神経学   52 ( 12 )   1400 - 1400   2012年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 本邦におけるc9FTD/ALSの遺伝・病理学的検討

    今野 卓哉, 志賀 篤, 辻野 彰, 加藤 泰介, 金井 数明, 横関 明男, 江口 博人, 桑原 聡, 西澤 正豊, 高橋 均, 小野寺 理

    臨床神経学   52 ( 12 )   1549 - 1549   2012年12月

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    記述言語:日本語   出版者・発行元:(一社)日本神経学会  

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  • 【認知症学 下-その解明と治療の最新知見-】 臨床編 血管性認知症とその類縁疾患 CADASIL(皮質下梗塞および白質脳症を伴う常染色体優性脳動脈症)とCARASIL(皮質下梗塞と白質脳症を伴う脳常染色体劣性動脈症)

    加藤 泰介, 西澤 正豊, 小野寺 理

    日本臨床   69 ( 増刊10 認知症学(下) )   320 - 324   2011年12月

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    記述言語:日本語   出版者・発行元:(株)日本臨床社  

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講演・口頭発表等

  • Gene therapy for DRPLA model mice by AAV-delivered CRISPR / Cas9

    Taisuke Kato, Sachiko Hirokawa, Kenta Kobayashi, Shoji Tsuji, Osamu Onodera

    Genome Engineering: From Mechanisms to Therapies, Keystone Symposia Conference  2019年2月 

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    開催年月日: 2019年2月

    記述言語:英語   会議種別:口頭発表(一般)  

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  • Therapeutic strategy based on genome editing by CRISPR/Cas9 for polyglutamine disease using DRPLA modelTherapeutic stra

    Taisuke Kato, Sachiko Hirokawa, Kenta Kobayashi, Shoji Tsuji, Osamu Onodera

    Advances in Neurodegenerative Disease Research and Therapy. Keystone Symposia Conference.  2018年6月 

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    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

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  • Serine protease HTRA1 deficiency induces arteriopathy in cerebral small vessels. 招待

    Taisuke Kato, Yumi Sekine, Natsumi Fujita, Hiroaki Nozaki, Sachiko Hirokawa, Toshiya Sato, Shoji Tsuji, Osamu Onodera

    2017年度生命科学系学会合同年次大会  2017年12月 

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    開催年月日: 2017年12月

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • セリンプロテアーゼHTRA1の機能欠損は、脳小血管病を引き起こす 招待

    Taisuke Kato, Yumi Sekine, Natsumi Fujita, Hiroaki Nozaki, Sachiko Hirokawa, Toshiya Sato, Osamu Onodera

    第40回日本神経科学大会  2017年7月 

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    開催年月日: 2017年7月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

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受賞

  • 夏のワークショップ若手優秀発表賞受賞

    2014年   包括型脳科学研究推進支援ネットワーク   筋萎縮性側索硬化症運動神経細胞におけるTDP-43 mRNAの細胞内局在解析

    加藤 泰介

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共同研究・競争的資金等の研究

  • 脳の排泄経路の解明による加齢性脳疾患へのアプローチ

    研究課題/領域番号:19H01043  2019年4月 - 2022年3月

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

    小野寺 理, 上村 昌寛, 五十嵐 博中, 今野 卓哉, 加藤 泰介, 清水 宏, 金澤 雅人

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    配分額:45500000円 ( 直接経費:35000000円 、 間接経費:10500000円 )

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  • 遺伝性脳小血管病変異TREX1の細胞内局在異常による毒性機能獲得メカニズムの解明

    研究課題/領域番号:18K07522  2018年4月 - 2021年3月

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

    加藤 泰介

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    RVCLは、脳・網膜の小血管を主に侵す優性遺伝性の脳小血管病であり、最終的には死に至る疾患であり治療法はない。本症の原因遺伝子はエキソヌクレアーゼの一つであるTREX1である。TREX1はRVCLの他にAGS、FCLの原因遺伝子、さらにSLEの感受性遺伝子としても知られている。AGS・SLE・FCLは自己免疫が関与する類縁疾患であるが、RVCLはこれらの疾患とは異なる病態を呈する。何故同一の遺伝子内の変異により、異なるスペクトラムのRVCLが発症するのかは分かっていない。申請者はRVCL変異TREX1特異的にDNA損傷応答シグナルが亢進することを見出しており、これがRVCL特異的な病態メカニズムに関与すると仮説を立て研究をスタートした。
    本年度は、次の点を明らかとした。①RVCL変異TREX1は、複数あるDNA損傷形式の中でも最も悪性度の高い2本差DNA損傷を引き起こす。②RVCL変異TREX1の発現は不死化細胞では細胞死を誘発するが、正常細胞では不可逆的な増殖停止を誘導する。RVCL変異TREX1の発現は内在性野生型TREX1タンパク質の発現を低下させるが、局在は変化させないこと。④RVCL変異TREX1のDNA損傷には核局在と、エキソヌクレアーゼが必要であること。また、これらの新規に知見に加えて、申請者はRVCLモデル生物としてゲノム編集を用いて内在性Trex1遺伝子にRVCL類似のフレームシフト変異を導入したモデルマウスとRVCL変異TREX1過剰発現ハエモデルを作製した。
    次年度以降は正常細胞安定発現細胞株を用いて、RVCL変異TREX1が細胞老化・SASPといった老化・炎症に関わる細胞機能変化を誘導するか、生体内においても同様のDNA損傷、細胞老化・SASPを誘導するかに関して集中的に研究を推進していく予定である。本研究は非常に順調にマイルストンを達成している。

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  • アストロサイトを侵すタウオパチー:タウの病理多様性とアストロサイト多様性の関係

    研究課題/領域番号:17H03554  2017年4月 - 2020年3月

    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)

    高橋 均, 小野寺 理, 加藤 泰介, 田中 英智, 豊島 靖子

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    配分額:17290000円 ( 直接経費:13300000円 、 間接経費:3990000円 )

    PSPとCBDはアストロサイト胞体内に4-リピートリン酸化タウ蓄積による封入体を認める疾患であるが、両疾患間でその封入体の形状や封入体含有アストロサイトの脳内分布が異なる。PSPではtufted astrocyte、CBDではastrocytic plaqueを示し、前者は明るく、やや大きい核の周辺から放射状にくねくね伸びる表面の滑らかな線状構造であるが、後者は太 く、短い、表面がギザギザしてみえる構造物である。また、PSPでは主に皮質、特に皮質深部に分布するのに対し、CBDでは皮質から白質まで広汎に認められる。それ故、これらの疾患では、その病的なアストロサイトの種類が異なると推察した。近年、アストロサイトは極めて複雑な、機能的に多様性に富む細胞であることが示唆されている。しかし、その分子マー カーは明らかとはなっていないため、免疫組織化学的にこれらを区別することは困難であった。我々は、両疾患においてリン酸化タウの蓄積を認めるアストロサイトの特性を解析する。今までに、PSPとCBD剖検脳を対象とし、両疾患で高頻度に異常アストロサイトを認める運動野を含む大脳のフォルマリン固定パラフィン包埋(FFPE)組織を用い、抗リン酸化タウ 抗体(clone AT8 , Innogenetics)を用いて免疫染色を行い,特徴的な封入体を持つアストロサイトを皮質にて同定し、Laser Capture Microdissection System(Leica LMD 7000:Leica 社)にて、1例につき100細胞を目安とし選択的回収を行うことを試みた。しかし、細胞範囲を同定することが困難であり、同定手法を再考する必要があることが判明した。よって、当該領域の組織を用いて解析を試み、得られた結果からクラスター解析を行い、PSPとCBDの皮質のアストロサイト間の差の検討を開始した。

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  • 脳小血管の動的機能に注目した脳血管性認知症克服への戦略

    研究課題/領域番号:16H02656  2016年4月 - 2019年3月

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

    小野寺 理, 豊島 靖子, 加藤 泰介, 小山 哲秀, 野崎 洋明

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    配分額:46670000円 ( 直接経費:35900000円 、 間接経費:10770000円 )

    認知症の克服は喫緊の課題であり、脳血管性認知症は主因の一つである。この病変として、脳の小血管が注目され脳小血管病と称される。この病態として、近年、神経活動依存性血流調節機構の障害が唱えられている。しかし、その分子病態は不明である。我々は遺伝性脳小血管病の原因遺伝子HTRA1を単離し、本症が組織増殖因子シグナルの亢進によることを明らかとした。さらに、非遺伝性の脳小血管病類似の平滑筋・周皮細胞の変性を伴うマウスにて脳小血管病の分子病態、特に、組織増殖因子シグナルによる小血管障害機構を明らかとした。

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  • TGFβシグナルの亢進は脳小血管病を引き起こすか?

    2014年4月 - 2015年3月

    文部科学省  科学研究費補助金 若手研究(B) 

    加藤 泰介

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    担当区分:研究代表者  資金種別:競争的資金

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  • 炎症による血液脳関門の破綻を転機としたCARASIL病態発症機序の解析

    研究課題/領域番号:11J07794  2011年 - 2013年

    日本学術振興会  科学研究費助成事業 特別研究員奨励費  特別研究員奨励費

    加藤 泰介

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    配分額:2400000円 ( 直接経費:2400000円 )

    High temperature requirement A1 (HTRA1)は遺伝性脳小血管病の一つであるCARASILの原因遺伝子であり、HtrA1遺伝子変異によるプロテアーゼ機能喪失/低下がこの疾患の発症原因であることが推測されている(N Eng J Med 2009)。本研究は、HTRA1機能喪失により実際にin vivoにてCARASIL病態が再現されうるかを中心に解析を進めてきた。さらに、CARASILの病態背景にはプロテアーゼであるHTRA1の基質であるTransforming growth factorβ (TGFβ)ファミリーのシグナル亢進が強く関与することが示唆されている。この仮説を検証するために、HTRA1機能喪失時に想定されるアストロサイトからのTGFβの分泌亢進を模倣するTGFβ1トランスジェニックマウス(TGFβ1-Tg)を用いてTGFβシグナル亢進がCARASIL病態を引き起こすかの検証を進めた。
    解析の結果、HtrA1ノックアウトマウス(HtrA1-KOマウス)は、加齢依存的に血管平滑筋細胞の変性、軟膜下血管腔の拡大、さらに脳毛細血管における周皮細胞の変性を示すことが明らかとなった。また、同様の解析をTGFβ1-Tgで進めた結果、HtrAl-KOマウスと同様のCARASIL類似の血管平滑筋細胞、周皮細胞の変性を加齢依存的に示すことが明らかとなった。
    以上の解析結果により、HtrA1の機能喪失が、実際に生体においてCARASIL病態を再現することが明らかとなり、HtrA1-KOマウスが有用な脳小血管病モデルであることが示された。またTGFβ1-Tgの結果から、CARASIL病態にはTGFβファミリーシグナルが関与することが強く示唆され、これらの結果は脳小血管病の分子メカニズムの解明に大きく寄与するものであると考えられる。

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