Roles of stress granules in the disease process of multiple system atrophy

• Project/Area Number: 26430049
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Hirosaki University
• Principal Investigator: MORI FUMIAKI 弘前大学, 医学研究科, 准教授 (60200383)
• Co-Investigator(Kenkyū-buntansha): 丹治 邦和 弘前大学, 医学研究科, 助教 (10271800) ; 若林 孝一 弘前大学, 医学研究科, 教授 (50240768)
• Co-Investigator(Renkei-kenkyūsha): MIKI YASUO 弘前大学, 大学院医学研究科, 助教 (30709142)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 多系統萎縮症 / MSA / αシヌクレイノパチー / 封入体 / ストレス顆粒 / RNA / RNA結合タンパク質 / HuR / 神経変性疾患 / αシヌクレイン / オートファジー / 封入体形成 / 遺伝子改変マウス

Outline of Final Research Achievements

Stress granules are cytoplasmic messenger ribonucleoprotein particles that form dense aggregations in the cytosol composed of RNAs and RNA binding proteins that appear when translation is impaired under stress conditions. Stress granuless are thought to play an important role in the pathogenesis of neurodegenerative diseases by acting as seeds for pathological inclusions. To elucidate the significance of formation of stress granule and protein aggregates in the disease process of multiple system atrophy, we examined dynamic changes of stress granule-related proteins and protein degradation systems using tissue samples from multiple system atrophy patients and normal controls and cell and animal models for alpha-synucleinopathy. These results suggested that stress granules marker proteins and protein degradation systems may be therapeutic targets to prevent multiple system atrophy.

Research Products

• [Journal Article] PLA2G6 accumulates in Lewy bodies in PARK14 and idiopathic Parkinson's disease. (2017)
  • Author(s): Miki Y, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neurosci Lett Volume: 645 Pages: 40-45
  • DOI: 10.1016/j.neulet.2017.02.027
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] AMBRA1, a novel alpha-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy. (2017)
  • Author(s): Miki Y, Tanji K, Mori F, Tatara Y, Utsumi J, Sasaki H, Kakita A, Takahashi H, Fimia GM, Wakabayashi K.
  • Journal Title: Brain Pathol Volume: 印刷中 Issue: 1 Pages: 28-42
  • DOI: 10.1111/bpa.12461
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MicroRNA expression profiles of multiple system atrophy from formalin-fixed paraffin-embedded samples. (2016)
  • Author(s): Wakabayashi K, Mori F, Kakita A, Takahashi H, Tanaka S, Utsumi J, Sasaki H.
  • Journal Title: Neurosci Lett Volume: 635 Pages: 117-122
  • DOI: 10.1016/j.neulet.2016.10.034
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel eosinophilic neuronal cytoplasmic inclusions in the external cuneate nucleus of humans (2016)
  • Author(s): Ito M, Nakamura K, Mori F, Miki Y, Tanji K, Wakabayashi K.
  • Journal Title: Neuropathology Volume: - Issue: 5 Pages: 441-447
  • DOI: 10.1111/neup.12292
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Accumulation of phosphorylated alpha-synuclein in subpial and periventricular astrocytes in multiple system atrophy of long duration (2016)
  • Author(s): Nakamura K, Mori F, Kon T, Tanji K, Miki Y, Tomiyama M, Kurotaki H, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K.
  • Journal Title: Neuropathology Volume: - Issue: 2 Pages: 157-167
  • DOI: 10.1111/neup.12243
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] alpha-Synuclein pathology in the cranial and spinal nerves in Lewy body disease (2016)
  • Author(s): Nakamura K, Mori F, Tanji K, Miki Y, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K.
  • Journal Title: Neuropathology Volume: - Issue: 3 Pages: 262-269
  • DOI: 10.1111/neup.12269
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The role of NUB1 in alpha-synuclein degradation in Lewy body disease model mice (2016)
  • Author(s): Tanji K, Miki Y, Maruyama A, Mori F, Mimura J, Itoh K, Kamitani T, Wakabayashi K.
  • Journal Title: Biochem Biophys Res Commun Volume: 470 Issue: 3 Pages: 635-642
  • DOI: 10.1016/j.bbrc.2016.01.093
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] G protein-coupled receptor 26 immunoreactivity in intranuclear inclusions associated with polyglutamine and intranuclear inclusion body diseases (2016)
  • Author(s): Mori F, Tanji K, Miki Y, Toyoshima Y, Yoshida M, Kakita A, Takahashi H, Utsumi J, Sasaki H, Wakabayashi K.
  • Journal Title: Neuropathology Volume: 36 Issue: 1 Pages: 50-55
  • DOI: 10.1111/neup.12237
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Alteration of Upstream Autophagy-Related Proteins (ULK1, ULK2, Beclin1, VPS34 and AMBRA1) in Lewy Body Disease (2016)
  • Author(s): Miki Y, Tanji K, Mori F, Utsumi J, Sasaki H, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Brain Pathol Volume: - Issue: 3 Pages: 359-370
  • DOI: 10.1111/bpa.12297
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sortilin-related receptor CNS expressed 2 (SorCS2) is localized to Bunina bodies in amyotrophic lateral sclerosis (2015)
  • Author(s): Mori F, Miki Y, Tanji K, Kakita A, Takahashi H, Utsumi J, Sasaki H, Wakabayashi K.
  • Journal Title: Neurosci Lett Volume: 608 Pages: 6-11
  • DOI: 10.1016/j.neulet.2015.09.030
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Trehalose intake induces chaperone molecules along with autophagy in a mouse model of Lewy body disease. (2015)
  • Author(s): Tanji K, Miki Y, Maruyama A, Mimura J, Matsumiya T, Mori F, Imaizumi T, Itoh K, Wakabayashi K.
  • Journal Title: Biochem Biophys Res Commun Volume: 465 Issue: 4 Pages: 746-752
  • DOI: 10.1016/j.bbrc.2015.08.076
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Nuclear receptor subfamily 4, group A, member 3 (NR4A3) is localized in Lewy bodies and neuronal and glial cytoplasmic inclusions in multiple system atrophy. (2015)
  • Author(s): 1.Kon T, Miki Y, Tanji K, Mori F, Tomiyama M, Toyoshima Y, Kakita A, Takahashi H, Utsumi J, Sasaki H, Wakabayashi K.
  • Journal Title: Neuropathology Volume: 印刷中
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Isopentenyl diphosphate isomerase, a cholesterol synthesizing enzyme, is localized in Lewy bodies. (2015)
  • Author(s): Nakamura K, Mori F, Tanji K, Miki Y, Masahito Y, Kakita A, Takahashi H, Wakabayashi K.
  • Journal Title: Neuropathology Volume: 印刷中
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] p62 Deficiency Enhances α-Synuclein Pathology in Mice. (2015)
  • Author(s): Tanji K, Odagiri S, Miki Y, Maruyama A, Nikaido Y, Mimura J, Mori F, Warabi E, Yanagawa T, Ueno S, Itoh K, Wakabayashi K.
  • Journal Title: Brain Pathol. Volume: 印刷中 Issue: 5 Pages: 552-564
  • DOI: 10.1111/bpa.12214
  • Peer Reviewed / Open Access
• [Journal Article] Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington’s disease (2014)
  • Author(s): Miki Y, Tanji K, Mori F, Wakabayashi K
  • Journal Title: Neurobiol Dis Volume: 74 Pages: 25-31
  • DOI: 10.1016/j.nbd.2014.11.005
  • NAID: 130008041715
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Analysis of microRNA from archived formalin-fixed paraffin-embedded specimens of amyotrophic lateral sclerosis (2014)
  • Author(s): Wakabayashi K, Mori F, Kakita A, Takahashi H, Utsumi J, Sasaki H
  • Journal Title: Acta Neuropathol Comm Volume: 2 Issue: 1 Pages: 173-173
  • DOI: 10.1186/s40478-014-0173-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] ポリグルタミン病および核内封入体病におけるRNA分解酵素の免疫組織化学的検討 (2017)
  • Author(s): 森文秋、三木康生、丹治邦和、豊島靖子、吉 田眞理、佐々木秀直、柿田明美、高橋均、若 林孝一
  • Organizer: 第58回日本神経病理学会総会学術研究会
  • Place of Presentation: 学術総合センター（一橋講堂）（東京）
  • Year and Date: 2017-06-01
• [Presentation] 天然糖質投与によるレビー小体病モデルマウスへの影響 (2017)
  • Author(s): 丹治邦和、三木康生、成田秀美、三村純正、森 文秋、伊東 健、若林孝一
  • Organizer: 第58回日本神経病理学会総会学術研究会
  • Place of Presentation: 学術総合センター（一橋講堂）（東京）
  • Year and Date: 2017-06-01
• [Presentation] PLA2G6はPARK14と特発性パーキンソン病のレヴィ小体に蓄積する (2017)
  • Author(s): 三木康生、丹治邦和、森文秋、柿田明美、高橋均、若林孝一
  • Organizer: 第58回日本神経病理学会総会学術研究会
  • Place of Presentation: 学術総合センター（一橋講堂）（東京）
  • Year and Date: 2017-06-01
• [Presentation] 多系統萎縮症の軟膜下および脳室周囲アストロサイトにおける (2016)
  • Author(s): 中村 桂子、森 文秋、今 智矢、丹治 邦和、三木 康生、冨山 誠彦、黒滝日出一、豊島 靖子、柿田 明美、高橋 均、山田 正仁、若林 孝一
  • Organizer: 日本神経病理学会
  • Place of Presentation: ホテルニューキャッスル（青森県・弘前市）
  • Year and Date: 2016-06-01
• [Presentation] Lewy 小体病の脳神経および脊髄神経におけるαシヌクレインの蓄積 (2016)
  • Author(s): 中村 桂子、森 文秋、丹治 邦和、三木 康生、豊島 靖子、柿田 明美、高橋 均、山田 正仁、若林 孝一
  • Organizer: 日本神経病理学会
  • Place of Presentation: ホテルニューキャッスル（青森県・弘前市）
  • Year and Date: 2016-06-01
• [Presentation] 延髄の外側楔状束核に認められた新規エオジン好性神経細胞内 (2016)
  • Author(s): 伊藤 真子、中村 桂子、森 文秋、三木 康生、丹治 邦和、若林 孝一
  • Organizer: 日本神経病理学会
  • Place of Presentation: ホテルニューキャッスル（青森県・弘前市）
  • Year and Date: 2016-06-01
• [Presentation] レビー小体病におけるsynphilin-1 結合タンパク質（NUB1）の役割 (2016)
  • Author(s): 丹治 邦和、三木 康生、丸山 敦史、森 文秋、三村 純正、伊東 健、神谷 哲、若林 孝一
  • Organizer: 日本神経病理学会
  • Place of Presentation: ホテルニューキャッスル（青森県・弘前市）
  • Year and Date: 2016-06-01
• [Presentation] 多系統萎縮症におけるオートファジー上流分子の異常 (2016)
  • Author(s): 三木 康生、丹治 邦和、森 文秋、内海 潤、佐々木秀直、柿田 明美、高橋 均、若林 孝一
  • Organizer: 日本神経病理学会
  • Place of Presentation: ホテルニューキャッスル（青森県・弘前市）
  • Year and Date: 2016-06-01
• [Presentation] ポリグルタミン病および核内封入体病におけるパラスペックル (2016)
  • Author(s): 森 文秋、三木 康生、丹治 邦和、豊島 靖子、吉田 眞理、佐々木秀直、柿田 明美、高橋 均、若林 孝一
  • Organizer: 日本神経病理学会
  • Place of Presentation: ホテルニューキャッスル（青森県・弘前市）
  • Year and Date: 2016-06-01
• [Presentation] オートファジー/ストレス顆粒関連蛋白陽性のエオジン好性封入体 (2014)
  • Author(s): 森 文秋、渡辺柚香、三木康生、丹治邦和、小田桐紗織、衞藤光明、若林孝一
  • Organizer: 日本神経病理学会
  • Place of Presentation: 学術総合センター（東京）
  • Year and Date: 2014-06-05 – 2014-06-07
• [Presentation] 脊髄小脳失調症2型脳に認められた2種類の核内封入体 (2014)
  • Author(s): 森 文秋、豊島靖子、丹治邦和、柿田明美、高橋 均、若林孝一
  • Organizer: 日本神経病理学会
  • Place of Presentation: 学術総合センター（東京）
  • Year and Date: 2014-06-05 – 2014-06-07