Treatment strategy of Lewy body disease by activation of intracellular degradation system

• Project/Area Number: 26860655
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Hirosaki University
• Principal Investigator: Miki Yasuo 弘前大学, 医学(系)研究科(研究院), 助教 (30709142)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: レビー小体病 / α-シヌクレイン / オートファジー / トレハロース / Beclin1 / αシヌクレイン / オートファジ― / ULK1 / ULK2 / VPS34 / AMBRA1

Outline of Final Research Achievements

The accumulation of mis-folded and/or abnormally modified proteins is a major characteristic of many neurodegenerative diseases. In Lewy body disease (LBD), insoluble α-synuclein is widely deposited in the presynaptic terminals as well as in the neuronal cytoplasm in distinct brain regions. The autophagy-lysosome system is an efficient degradation pathway for abnormal molecules within cells. We investigated the effect of trehalose on abnormal aggregation of α-synuclein in a model of LBD. Trehalose treatment induced autophagy and reduced level of detergent-insoluble α-synuclein, although an apparent alteration was not observed in abnormal aggregation of α-synuclein. These results indicate that the oral intake of trehalose can be a promissing treatment for prevention of accumulation of abnormal α-synuclein, especially before aggregation formation.

Research Products

• [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] 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] 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] 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] 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] Localization of nuclear receptor subfamily 4, group A, member 3 (NR4A3) in Lewy body disease and multiple system atrophy (2015)
  • Author(s): 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: 35 Issue: 6 Pages: 503-509
  • DOI: 10.1111/neup.12210
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] An autopsy case of refractory epilepsy due to unilateral polymicrogyria in a 65-year-old man: Histogenesis of four-layered polymicrogyric cortex (2015)
  • Author(s): Miki Y, Tanji K, Mori F, Sakamoto N, Wakabayashi K
  • Journal Title: Neuropathology Volume: 35 Issue: 6 Pages: 569-574
  • DOI: 10.1111/neup.12219
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Filamentous aggregations of phosphorylated α-synuclein in Schwann cells (Schwann cell cytoplasmic inclusions) in multiple system atrophy (2015)
  • 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: Acta Neuropathol Commun Volume: 3 Issue: 1 Pages: 29-29
  • DOI: 10.1186/s40478-015-0208-0
  • Peer Reviewed / Open Access / Int'l Joint Research / 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, Yamada M, Kakita A, Takahashi H, Utsumi J, Sasaki H, Wakabayashi K
  • Journal Title: Neuropathol Volume: 35 Issue: 5 Pages: 432-440
  • DOI: 10.1111/neup.12204
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington's disease. (2015)
  • Author(s): Miki Y, Tanji K, Mori F, Wakabayashi K
  • Journal Title: Neurobiology of Disease Volume: 74 Pages: 25-31
  • NAID: 130008041715
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] p62 Deficiency Enhances α-Synuclein Pathology in Mice. (2014)
  • 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 Pathology Volume: -
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 左大脳半球に広範に多小脳回を認め、てんかんの焦点と考えられた１剖検例 (2015)
  • Author(s): 三木康生、丹治邦和、森文秋、阪本奈美子、若林孝一
  • Organizer: 第56回日本神経病理学会総会学術研究会
  • Place of Presentation: 福岡
  • Year and Date: 2015-06-03 – 2015-06-05
• [Presentation] オートファジー関連タンパク質（ULK1、ULK2、VPS34、AMBRA1）はレビー小体の形成過程に関与している (2015)
  • Author(s): 三木康生、丹治邦和、森文秋、柿田明美、高橋均、内海潤、佐々木秀直、若林孝一
  • Organizer: 第56回日本神経病理学会総会学術研究会
  • Place of Presentation: 福岡
  • Year and Date: 2015-06-03 – 2015-06-05
• [Presentation] Involvement of the sigma-1 receptor in neuronal nuclear aggregate formation in mutant Huntingtin induced cells (2014)
  • Author(s): Yasuo Miki, Kunikazu Tanji, Tomoya Kon, Fumiaki Mori, Koichi Wakabayashi
  • Organizer: XVIII International Congress of Neuropathology
  • Place of Presentation: Brazil
  • Year and Date: 2014-09-14 – 2014-09-18
• [Presentation] Incipient Pick diseaseの1剖検例 (2014)
  • Author(s): 三木康生, 森文秋, 丹治邦和, 黒滝日出一, 柿田明美, 高橋均, 若林孝一
  • Organizer: 第55回日本神経病理学会総会学術研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-06-05 – 2014-06-07
• [Presentation] Sigma-1 receptorの蓄積は種々の神経変性疾患の核内封入体に共通する。 (2014)
  • Author(s): 三木康生、森文秋、今智矢、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55回日本神経病理学会総会学術研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-06-05 – 2014-06-07