Biochemical and neuropathological analysis of HtrA2 knockout mouse

2011 Fiscal Year Final Research Report

• Project/Area Number: 21500336
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Kyoto University
• Principal Investigator: ITO Hidefumi 京都大学, 医学研究科, 講師 (20250061)
• Co-Investigator(Kenkyū-buntansha): TAKAHASHI Ryosuke 京都大学, 医学研究科, 教授 (90216771) ; KAWAMOTO Yasuhiro 京都大学, 医学研究科, 非常勤講師 (40335253)
• Project Period (FY): 2009 – 2011
• Keywords: パーキンソン病 / HtrA2 / knockout mouse

Research Abstract

We generated HtrA2 knockout(KO) mice, and analyzed them biochemically and neuropathologically. We found that the mean survival of the homozygous HtrA2 KO mice was 30 days. In the mice, the striatum was degenerated and ubiquitinated proteins were accumulated. In addition, we found reduction of COXI, COXIV, and parkin proteins, and increase of LC3-II. Their skeletal and cardiac muscles showed atrophy. The mean survival of HtrA2/parkin double KO mice was shorter than that of HtrA2 KO mice. Moreover, we identified HtrA2 immunoreactivity in the senile plaques and the neurofibrillary tangles of Alzheimer's and in the intracytoplasmic inclusions of ALS patients.

Research Products

• [Journal Article] Cilostazol, a phosphodiesterase inhibitor, prevents no-reflow and hemorrhage in mice with focal cerebral ischemia (2012)
  • Author(s): Hase Y, Okamoto Y, Fujita Y, KitamuraA, Ito H, Maki T, Washida K, TakahashiR, Ihara M
  • Journal Title: Experimental Neurology Volume: 233 Pages: 523-533
  • DOI: DOI:10.1016/j.expneurol.2011.11.038
  • Peer Reviewed
• [Journal Article] Selective white matter abnormalities in a novel rat model of vascular dementia (2012)
  • Author(s): Kitamura A, Fujita Y, Oishi N, KalariaR N, Washida K, Maki T, Okamoto Y, HaseY, Yamada M, Takahashi J, Ito H, Tomimoto H, Fukuyama H, Takahashi R, Ihara M
  • Journal Title: Neurobiology of Aging Volume: 33 Pages: 1012. e25-1012. e35
  • DOI: DOI:10.1016/j.neurobiolaging.2011.10.033
  • Peer Reviewed
• [Journal Article] Environmental enrichment ameliorated high fat diet-induced Aβdeposition and memory deficit in APP transgenic mice (2012)
  • Author(s): Maesako M, Uemura K, Kubota M, Kuzuya A, Sasaki K, Asada M, Watanabe K, Hayashida N, Ihara M, Ito H, ShimohamaS, Kihara T, Kinoshita A
  • Journal Title: Neurobiology of Aging Volume: 33 Pages: 1011. e11-1011. e23
  • DOI: DOI:10.1016/j.neurobiolaging.2011.10.028
  • Peer Reviewed
• [Journal Article] Protein disulfide isomerase immunopositivei nclusions in patients with amyotrophic lateral sclerosis (2011)
  • Author(s): Honjo Y, Kaneko S, Ito H, Horibe T, Takahashi R, Kawakami K
  • Journal Title: Amyotrophic lateral sclerosis Volume: 12 Pages: 444-450
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22174512
  • Peer Reviewed
• [Journal Article] Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation (2011)
  • Author(s): Ito H, Nakamura M, Komure O, Ayaki T, Wate R, Maruyama H, Nakamura Y, FujitaK, Kaneko S, Okamoto Y, Ihara M, Konishi T, Ogasawara K, Hirano A, Kusaka H, KajiR, Takahashi R, Kawakami H
  • Journal Title: Acta Neuropathologica Volume: 122 Pages: 223-229
  • DOI: DOI:10.1007/s00401-011-0842-y
  • Peer Reviewed
• [Journal Article] Watershed Infarcts in a multiple microembolic model of monkey (2011)
  • Author(s): Maki T, Wakita H, Mase M, Itagaki I, Saito N, Ono F, Adachi K, Ito H, Takahashi R, Ihara M, Tomimoto H
  • Journal Title: Neuroscience Letters Volume: 499 Pages: 80-83
  • DOI: DOI:10.1016/j.neulet.2011.05.036
  • Peer Reviewed
• [Journal Article] Protein disulfide isomerase immuno positive glial cytoplasmic inclusions in patients with multiple system atrophy (2011)
  • Author(s): Honjo Y, Ito H, Horibe T, Takahashi R, Kawakami K
  • Journal Title: International Journal of Neuroscience
  • DOI: DOI:10.3109/00207454.2011.585440
  • Peer Reviewed
• [Journal Article] Co localization of 14-3-3 proteins with SOD1 in Lewy Body-like hyaline inclusions in familial amyotrophic lateral sclerosis cases and the animal model (2011)
  • Author(s): Okamoto Y, Shirakashi Y, Ihara M, Urushitani M, Oono M, Kawamoto Y, Yamashita H, Shimohama S, Kato S, Hirano A, Tomimoto H, Ito H, Takahashi R
  • Journal Title: PLoS One Volume: 6 Pages: e20427
  • DOI: DOI:10.1371/journal.pone.0020427
  • Peer Reviewed
• [Journal Article] Angiogenic roles of adreno medullin through VEGF induction (2011)
  • Author(s): Maki T, Ihara M, Fujita Y, Nambu T, Harada H, Ito H, Nakao K, Tomimoto H, Takahashi R
  • Journal Title: Neuroreport Volume: 22 Pages: 442-447
  • DOI: DOI:10.1097/WNR.0b013e32834757e4
  • Peer Reviewed
• [Journal Article] Optineurin is co-localized with FUS in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease (2011)
  • Author(s): Ito H, Fujita K, Nakamura M, Wate R, Kaneko S, Sasaki S, Yamane K, Suzuki N, Aoki M, Shibata N, Togashi S, Kawata A, Mochizuki Y, Mizutani T, Maruyama H, Hirano A, Takahashi R, Kawakami H, Kusaka H
  • Journal Title: Acta Neuropathologica Volume: 121 Pages: 555-557
  • DOI: DOI:10.1007/s00401-011-0809-z
  • Peer Reviewed
• [Journal Article] The influence of chronic cerebral hypoperfusion on cognitive function and amyloid b metabolism in APP overexpressing mice (2011)
  • Author(s): Yamada M, Ihara M, Okamoto Y, Maki T, Washida K, Kitamura A, Hase Y, Ito H, Takao K, Miyakawa T, Kalaria RN, Tomimoto H, Takahashi R
  • Journal Title: PLoS One Volume: 6 Pages: e16567
  • DOI: DOI:10.1371/journal.pone.0016567
  • Peer Reviewed
• [Journal Article] Angiogenic and vasoprotective effects of adreno medulin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice (2011)
  • Author(s): Maki T, Ihara M, Fujita Y, Nambu T, Miyashita K, Yamada M, Washida K, Nishio K, Ito H, Harada H, Yokoi H, Arai H, Itoh H, Nakao K, Takahashi R, Tomimoto H
  • Journal Title: Stroke Volume: 42 Pages: 1122-1128
  • DOI: DOI:10.1161/STROKEAHA.110.603399
  • Peer Reviewed
• [Journal Article] Ammonium chloride and tunicamycin are novel toxins for dopaminergic neurons and induce Parkinson's disease-like phenotypes in medaka fish (2010)
  • Author(s): Matsui H, Ito H, Taniguchi Y, Takeda S, Takahashi R
  • Journal Title: Journal of Neurochemistry Volume: 115 Pages: 1150-1160
  • DOI: DOI:10.1111/j.1471-4159.2010.07012.x
  • Peer Reviewed
• [Journal Article] Localization of HtrA2/Omi immunoreactivity in brains with Alzheimer's disease (2010)
  • Author(s): Kawamoto Y, Ito H, Ihara M, Kobayashi Y, Suzuki Y, Takahashi R
  • Journal Title: Neuroreport Volume: 21 Pages: 1121-1125
  • DOI: DOI:10.1097/WNR.0b013e328340a731
  • Peer Reviewed
• [Journal Article] Smad ubiqui tination regulatory factor-2 in progressive supranuclear palsy (2010)
  • Author(s): Nakamura M, Ito H, Nakamura Y, Wate R, Kaneko S, Nakano S, Matsumoto S, Kusaka H
  • Journal Title: Neuropathology and Applied Neurobiology Volume: 37 Pages: 307-314
  • DOI: DOI:10.1111/j.1365-2990.2010.01120.x
  • Peer Reviewed
• [Journal Article] Early protective effect of bone marrow mononuclear cells against ischemic white matter damage through augmentation of cerebral blood flow (2010)
  • Author(s): Fujita Y, Ihara M, Ushiki T, Hirai H, Kizaka-kondoh S, Hiraoka M, Ito H, Takahashi R
  • Journal Title: Stroke Volume: 41 Pages: 2938-2943
  • DOI: DOI:10.1161/STROKEAHA.110.596379
  • Peer Reviewed
• [Journal Article] Proteasome inhibition in medaka brain induces the features of Parkinson disease (2010)
  • Author(s): Matsui H, Ito H, Taniguchi Y, Inoue H, Takeda S, Takahashi R
  • Journal Title: Journal of Neurochemistry Volume: 115 Pages: 178-187
  • DOI: DOI:10.1111/j.1471-4159.2010.06918.x
  • Peer Reviewed
• [Journal Article] Nonhypotensive dose of telmisartan attenuates cognitive impairment partially due to PPAR-γactivation in mice with chronic cerebral hypoperfusion (2010)
  • Author(s): Washida K, Ihara M, Nishio K, Fujita Y, Takahashi J, Wu X, Kihara T, Ito H, Tomimoto H, Takahashi R
  • Journal Title: Stroke Volume: 41 Pages: 1798-1806
  • DOI: DOI:10.1161/STROKEAHA.110.583948
  • Peer Reviewed
• [Journal Article] Protein disulfide 1somerase-immunopositive inclusions in patients with Alzheimer disease (2010)
  • Author(s): Honjo Y, Ito H, Horibe T, Takahashi R, Kawakami K
  • Journal Title: Brain Research Volume: 1349 Pages: 90-963
  • DOI: DOI:10.1016/j.brainres.2010.06.016
  • Peer Reviewed
• [Journal Article] Mutations of optineurin in amyotrophic lateral sclerosis (2010)
  • Author(s): Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, K
  • Journal Title: Nature Volume: 465 Pages: 223-226
  • DOI: DOI:10.1038/nature08971
  • Peer Reviewed
• [Journal Article] A mouse model characterizing features of vascular dementia with hippocampal atrophy (2010)
  • Author(s): Nishio K, Ihara M, Yamasaki N, KalariaRN, Maki T, Fujita Y, Ito H, Oishi N, Fukuyama H, Miyakawa T, Takahashi R, Tomimoto H
  • Journal Title: Stroke Volume: 41 Pages: 1278-1284
  • DOI: DOI:10.1161/STROKEAHA.110.581686
  • Peer Reviewed
• [Journal Article] HtrA2/Omi-immunoreactive intraneuronal inclusions in the anterior horn of patients with sporadic and SOD1 mutant amyotrophic lateral sclerosis (2010)
  • Author(s): Kawamoto Y, Ito H, Kobayashi Y, Suzuki Y, Akiguchi I, Fujimura H, Sakoda S, Kusaka H, Hirano A, Takahashi R
  • Journal Title: Neuropathology and Applied Neurobiology Volume: 36 Pages: 331-344
  • DOI: DOI:10.1111/j.1365-2990.2010.01075.x
  • Peer Reviewed
• [Journal Article] Nuclear Contour Irregularity and Abnormal Transporter Protein Distribution in Anterior Horn Cells in ALS (2009)
  • Author(s): Kinoshita Y, Ito H, Hirano A, Fujita K, Wate R, Nakamura M, Kaneko S, Nakano S, Kusaka H
  • Journal Title: Journal of Neuropathology and Experimental Neurology Volume: 68 Pages: 1184-1192
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/19816199
  • Peer Reviewed
• [Journal Article] Intra-bone marrow-bone marrow transplantation slows disease progression and prolongs survival in G93A mutant SOD1 transgenic mice, an animal model mouse for amyotrophic lateral sclerosis (2009)
  • Author(s): Ohnishi S, Ito H, Suzuki Y, Adachi Y, Wate R, Zhang JH, Nakano S, Kusaka H, Ikehara S
  • Journal Title: Brain Research Volume: 1296 Pages: 216-224
  • DOI: DOI:10.1016/j.brainres.2009.08.012
  • Peer Reviewed
• [Journal Article] Cortical microinfarcts in Alzheimer's disease and subcortical vascular dementia (2009)
  • Author(s): Okamoto Y, Ihara M, Fujita Y, Ito H, Takahashi R, Tomimoto H
  • Journal Title: Neuroreport Volume: 20 Pages: 990-996
  • DOI: DOI:10.1097/WNR.0b013e32832d2e6a
  • Peer Reviewed
• [Journal Article] Screening for TARDBP mutations in Japanese familial amyotrophic lateral sclerosis (2009)
  • Author(s): Kamada M, Maruyama H, Tanaka E, Morino H, Wate R, Ito H, Kusaka H, Kawano Y, Miki T, Nodera H, Izumi Y, Kaji R, Kawakami H
  • Journal Title: Journal of The Neurological Sciences Volume: 284 Pages: 69-71
  • DOI: DOI:10.1016/j.jns.2009.04.017
  • Peer Reviewed
• [Presentation] Alzheimer病患者脳内におけるHtrA2/Omiの免疫組織化学的検討 (2011)
  • Author(s): 河本恭裕、伊東秀文, 他
  • Organizer: 第52回日本神経病理学会
  • Place of Presentation: 京都
  • Year and Date: 2011-06-04
• [Presentation] Optineurin in ALS (2011)
  • Author(s): Kawakami H, Maruyama H, Ito H
  • Organizer: AAN-JSN Joint Symposium
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2011-05-18
• [Presentation] 脳幹型および皮質型Lewy小体におけるXIAPとHtrA2/Omiの共存 (2011)
  • Author(s): 河本恭裕、伊東秀文, 他
  • Organizer: 第52回日本神経学会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Presentation] OPTN and Motor neuron disease (2011)
  • Author(s): Kawakami H, Maruyama H, Ito H
  • Organizer: International Symposium on Motor Neuron Disease and Perry Syndrome
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2011-02-22
• [Presentation] Cortical microinfarcts are related to cerebral amyloid angiopathy rather than to senile plaques or neurofibrillary tangles (2010)
  • Author(s): Okamoto Y, Ihara M, Ito H, Yamamoto T, Tomimoto H, Takahashi R
  • Organizer: The 40th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 20101113-17
• [Presentation] Clinical and Neuropathologic Investigation of a Family with ALS Associated with Mutated Optineurin (2010)
  • Author(s): Ito H, Nakamura M, Komure O, Maruyama M, Wate R, Nakamura Y, Fujita K, Kaneko S, Ogasawara O, Nakabayashi H, Ayaki T, Okamoto Y, Ihara M, Kaji R, Kusaka H, Hirano A, Takahashi R, Kawakami H
  • Organizer: XVIIth International Congress of Neuropathology
  • Place of Presentation: Salzburg, Austria
  • Year and Date: 20100912-15
• [Presentation] Smad ubiquitination regulatory factor-2 in progressive supranuclear palsy (2010)
  • Author(s): Nakamura M, Ito H, Kaneko S, Asayama S, Nakamura S, Nishii M, Fujita K, Matsumoto S, Kusaka H
  • Organizer: XVIIth International Congress of Neuropathology
  • Place of Presentation: Salzburg, Austria
  • Year and Date: 20100912-15
• [Presentation] An immunohistochemical study on basophilic inclusions of adult-onset atypical motor neuron disease (2010)
  • Author(s): Fujita K, Kaneko S, Ito H, Nishii M, Wate R, Nakano S, Kusaka H
  • Organizer: XVIIth International Congress of Neuropathology
  • Place of Presentation: Salzburg, Austria
  • Year and Date: 20100912-15
• [Presentation] Cortical microinfarcts are related to cerebral amyloid angiopathy rather than to senile plaques or neurofibrillary tangles (2010)
  • Author(s): Okamoto Y, Ihara M, Ito H, Yamamoto T, Tomimoto H, Takahashi R
  • Organizer: XVIIth International Congress of Neuropathology
  • Place of Presentation: Salzburg, Austria
  • Year and Date: 20100912-15
• [Presentation] A Mouse Model Characterizing Features of Vascular Dementia with Hippocampal Atrophy (2010)
  • Author(s): Ihara M, Nishio K, Kakaria RN, Maki T, Fujita Y, Ito H, Oishi N, Fukuyama H, Takahashi R, Tomimoto H
  • Organizer: XVIIth International Congress of Neuropathology
  • Place of Presentation: Salzburg, Austria
  • Year and Date: 20100912-15
• [Presentation] OPTN遺伝子変異例の臨床病理学的検討 (2010)
  • Author(s): 伊東秀文
  • Organizer: 厚生労働省障害者対策総合研究事業(神経・筋疾患分野) ALS/ALSD/FTLDU Consortium 2010サマーワークショップ特別講演
  • Place of Presentation: 東京
  • Year and Date: 2010-08-28
• [Presentation] Alzheimer病患者脳内におけるOmi/HtrA2の免疫組織化学的検討 (2010)
  • Author(s): 河本恭裕、伊東秀文, 他
  • Organizer: 第51回日本神経学会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-22
• [Presentation] ガイドラインに基づいたパーキンソン病の非運動症状の治療 (2010)
  • Author(s): 伊東秀文
  • Organizer: 第51回日本神経学会総会スポンサードセミナー
  • Place of Presentation: 東京
  • Year and Date: 2010-05-20
• [Presentation] The protective effect of telmisartan against chronic cerebral hypoperfusion in mice (2009)
  • Author(s): Washida K, Takahashi R, Takahashi J, Wu X, Kihara T, Tomimoto H, Ihara M, Ito H
  • Organizer: The 39th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Chicago, USA
  • Year and Date: 20091117-21
• [Presentation] Adrenomedullin promotes angiogenesis and arteriogenesis and preserves white matter integrity after chronic cerebral hypoperfusion in mice (2009)
  • Author(s): Maki T, Fujita Y, Ihara M, Ito H, Tomimoto H, Takahashi R
  • Organizer: The 39th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Chicago, USA
  • Year and Date: 20091117-21
• [Presentation] Protective effect of Cilostazol against the no-reflow phenomenon in transient cerebral ischemia (2009)
  • Author(s): Hase Y, Ihara M, Fujita Y, Ito H, Takahashi R
  • Organizer: The 39th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Chicago, USA
  • Year and Date: 20091117-21
• [Presentation] Cortical microinfarcts in Alzheimer's disease and subcortical vascular dementia (2009)
  • Author(s): Okamoto Y, Ihara M, Fujita Y, Ito H, Tomimoto H, Takahashi R
  • Organizer: The 39th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Chicago, USA
  • Year and Date: 20091117-21
• [Presentation] Effect of treatment with bone marrow mononuclear cells in a mouse model of chronic cerebral hypoperfusion (2009)
  • Author(s): Fujita Y, Ihara M, Ito H, Takahashi R
  • Organizer: The 39th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Chicago, USA
  • Year and Date: 20091107-21
• [Presentation] 筋萎縮性側索硬化症患者の脊髄前角細胞におけるOmi/HtrA2の集積 (2009)
  • Author(s): 河本恭裕、伊東秀文, 他
  • Organizer: 第50回日本神経病理学会
  • Place of Presentation: 高松
  • Year and Date: 2009-06-05
• [Book] これからのパーキンソン病治療「ガイドラインサポートハンドブックパーキンソン病」武田篤編 (2011)
  • Author(s): 伊東秀文
  • Total Pages: 207-218
  • Publisher: 医薬ジャーナル社
• [Book] パーキンソン病「ガイドライン外来診療2011」泉孝英編 (2011)
  • Author(s): 伊東秀文、高橋良輔
  • Total Pages: 486-488
  • Publisher: 日経メディカル開発
• [Book] パーキンソン症候群(SND, PSP, CBD)「研修医のための神経内科診療」阿部康二編 (2010)
  • Author(s): 伊東秀文、高橋良輔
  • Total Pages: 196-201
  • Publisher: 新興医学出版社
• [Remarks]
  • URL: http://www.kuhp.kyoto-u.ac.jp/~neurology/
• [Patent(Industrial Property Rights)] TDP-43の凝集体が蓄積する疾患の発症リスクを予測する方法、診断薬及び治療薬 (2012)
  • Inventor(s): 漆谷真、藤原範子、伊東秀文
  • Industrial Property Rights Holder: 滋賀医科大学、兵庫医科大学、京都大学
  • Industrial Property Number: 特願、2012-028737
  • Filing Date: 2012-02-13