Roles of ATF6 in MPTP/P-induced neurotoxicity and protein aggregation

• Project/Area Number: 23500440
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Kanazawa University
• Principal Investigator: HORI OSAMU 金沢大学, 医学系, 教授 (60303947)
• Co-Investigator(Renkei-kenkyūsha): KITAO Yasuko 金沢大学, 医学系, 准教授 (00019613) ; TAKARADA Mika 金沢大学, 医学系, 助教 (40565412)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 神経細胞死 / アストロサイト / 脳神経疾患 / 小胞体ストレス / 細胞死

Research Abstract

Accumulating evidence suggests a crucial role for the unfolded protein response (UPR) in Parkinson's disease (PD). In this study, we investigated the relevance of the UPR in a mouse model of chronic MPTP/probenecid (MPTP/P) injection. Enhanced activation of the UPR branches, including ATF6 and PERK, was observed after MPTP/P injections. Deletion of the ATF6 gene accelerated neuronal degeneration and ubiquitin accumulation. Surprisingly, astroglial activation was suppressed, and production of the brain-derived neurotrophic factor (BDNF) in astrocytes were reduced in ATF6 -/- mice after MPTP/P injections. In contrast, administration of the UPR-activating reagent tangeretin (IN19) enhanced the expression of UPR-target genes in both dopaminergic neurons and astrocytes, and promoted neuronal survival. These results suggest that the UPR is activated in a mouse PD model, and contributes to the survival of nigrostriatal dopaminergic neurons, in part, through activated astrocytes.

Research Products

• [Journal Article] Anxiety- and depression-like behavior in mice lacking the CD157/BST1 gene, a risk factor for Parkinson's disease. (2014)
  • Author(s): Lopatina O, Yoshihara T, Nishimura T, Zhong J, Akther S, Fakhrul AA, Liang M, Higashida C, Sumi K, Furuhara K, Inahata Y, Huang JJ, Koizumi K, Yokoyama S, Tsuji T, Petugina Y, Sumarokov A, Salmina AB, Hashida K, Kitao Y, Hori O, Asano M, Kitamura Y, Kozaka T, Shiba K, Zhong F, Xie MJ, Sato M, Ishihara K, Higashida H.
  • Journal Title: Front Behav Neurosci Volume: 8 Pages: 1-18
  • DOI: 10.3389/fnbeh.2014.00133
  • Peer Reviewed / Open Access
• [Journal Article] 4-dihydroxybenzalacetone protects against Parkinson's disease-related neurotoxin 6-OHDA through Akt/Nrf2/glutathione pathway (2013)
  • Author(s): Gunjima K, Tomiyama R, Takakura K, Yamada T, Hashida K, Nakamura Y, Konishi T, Matsugo S, Hori O
  • Journal Title: J Cell Biochem Volume: 115 Issue: 1 Pages: 151-160
  • DOI: 10.1002/jcb.24643
  • Peer Reviewed
• [Journal Article] ATF6alpha promotes astroglial activation and neuronal survival in a chronic mouse model of Parkinson's disease (2012)
  • Author(s): Hashida K, Kitao Y, Sudo H, Awa Y, Maeda S, Mori K, Takahashi R, Iinuma M, Hori O
  • Journal Title: PLoS One Volume: 7(10) Issue: 10 Pages: e47950-e47950
  • DOI: 10.1371/journal.pone.0047950
  • Peer Reviewed
• [Journal Article] ATF6alpha promotes astroglial activation and neuronal survival in a chronic mouse model of Parkinson's disease. (2012)
  • Author(s): Hashida K, Kitao Y, Sudo H, Awa Y, Maeda S, Mori K, Takahashi R, Iinuma M, Hori O.
  • Journal Title: PLoS One Volume: 7(10)
  • Peer Reviewed
• [Presentation] マウスパーキンソン病モデル(MPTPP/P 慢性投与モデル)における小胞体ストレス応答の重要性 (2013)
  • Author(s): 堀 修
  • Organizer: 第118回日本解剖学会・全国学術集会
  • Place of Presentation: サンポートホール高松, 香川県
• [Presentation] マウスパーキンソン病モデル（MPTPP/P慢性投与モデル）における小胞体ストレス応答の重要性 (2013)
  • Author(s): 堀 修
  • Organizer: 第118回日本解剖学会・全国学術集会
  • Place of Presentation: サンポートホール高松、香川県
• [Presentation] マウスパーキンソン病モデル(MPTPP/P 慢性投与モデル)における小胞体ストレス応答の重要性 (2012)
  • Author(s): 橋田耕治, 堀 修
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場, 福岡県
• [Presentation] 中枢神経系における小胞体ストレス応答の重要性 (2012)
  • Author(s): 堀 修
  • Organizer: 第24回日本脳循環代謝学会
  • Place of Presentation: リーガロイヤルホテル広島, 広島県
  • Invited
• [Presentation] マウスパーキンソン病モデル（MPTPP/P慢性投与モデルにおける小胞体ストレス応答の重要性 (2012)
  • Author(s): 橋田耕治、堀 修
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場、福岡県
• [Presentation] 中枢神経系における小胞体ストレス応答の重要性 (2012)
  • Author(s): 堀 修
  • Organizer: 第24回日本脳循環代謝学会
  • Place of Presentation: リーガロイヤルホテル広島、広島県
  • Invited
• [Presentation] Roles of the unfolded protein response (UPR) in MPTP-induced neurotoxicity (2011)
  • Author(s): 堀 修
  • Organizer: 第54回日本神経化学会大会(シンポジウム)
  • Place of Presentation: 山代温泉瑠璃光(石川県)
  • Year and Date: 2011-09-28
• [Presentation] MPTP/プロベネシド慢性投与パーキンソン病モデルにおける小胞体ストレス応答の重要性 (2011)
  • Author(s): 堀 修
  • Organizer: 第84回日本生化学会大会(シンポジウム)
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2011-09-22
• [Presentation] Deletion of ATF6α causes glial death and delayed neuronal damage after middle cerebral artery occlusion in mice
  • Author(s): Yasuko Kitao, Osamu Hori et al.
  • Organizer: Neuro2013
  • Place of Presentation: 京都
• [Presentation] MPTP/プロベネシド慢性投与パーキンソン病モデルにおける小胞体ストレス応答の重要性
  • Author(s): 堀 修
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都府）
• [Presentation] Roles of the unfolded protein response (UPR) in MPTP-induced neurotoxicity
  • Author(s): 堀 修
  • Organizer: 第54回日本神経化学会大会
  • Place of Presentation: 山代温泉瑠璃光（石川県）
• [Presentation] マウスパーキンソン病モデル（MPTPP/P慢性投与モデル）における小胞体ストレスの誘導
  • Author(s): 堀 修
  • Organizer: 日本解剖学会第71回中部支部学術集会
  • Place of Presentation: 名古屋大学（愛知県）
• [Remarks]
  • URL: http://med03.w3.kanazawa-u.ac.jp/