Establishment of a Perry syndrome disease model using human induced pluripotent stem cells

• Project/Area Number: 18K15471
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Fukuoka University
• Principal Investigator: Mishima Takayasu 福岡大学, 医学部, 講師 (00600602)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: Perry症候群 / Perry病 / DCTN1 / TDP-43 / 疾患モデル / iPS細胞

Outline of Final Research Achievements

We reported two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. With regard to basic research, our heterozygous Dctn1 G71A mice showed depression-like behavior, motor deficits, and a functional reduction in substantia nigral neurons, by TH immunostaining, thereby exhibiting multiple features of Perry disease (Perry syndrome). Furthermore, we found that dynactin1 bound to TDP-43. Biochemical analysis revealed that the dynactin CAP-Gly-basic supra-domain, dynactin domain, and C-terminal region interacted with TDP-43, preferentially through its C-terminal region. We thus revealed DCTN1 as a new player in TDP-43 cytoplasmic-nuclear transport, and showed that dysregulation of DCTN1-TDP-43 interactions triggers mislocalization and aggregation of TDP-43.

Academic Significance and Societal Importance of the Research Achievements

Perry病（Perry症候群）はパーキンソニズム、うつやアパシー、体重減少、中枢性呼吸障害の4徴候を有する常染色体優性（顕性）遺伝の神経変性疾患で、2009年にDCTN1遺伝子変異が発見された。また、病理学的には、筋萎縮性側索硬化症（ALS）などと同様にTDP-43プロテイノパチーに分類される。我々は、Perry病（Perry症候群）の国際診断基準を作成し、Perry症候群からPerry病への名称変更を提唱した。Perry病（Perry症候群）の研究は、パーキンソン病やALSなどの神経変性疾患の病態解明や治療薬開発だけでなく、うつ病や肥満などのコモンディジーズの研究にも寄与する。

Research Products

• [Int'l Joint Research] 米国スクリプス研究所(米国)
• [Int'l Joint Research] Mayo Clinic Jacksonville(米国)
• [Int'l Joint Research] Mayo Clinic Jacksonville(米国)
• [Int'l Joint Research] Mayo Clinic Jacksonville(米国)
• [Journal Article] Behavioral profile in a Dctn1 G71A knock-in mouse model of Perry disease (2021)
  • Author(s): Deshimaru M, Mishima T, Watanabe T, Kubota K, Hosoi M, Kinoshita-Kawada M, Yuasa-Kawada J, Ikeda M, Mori M, Murata Y, Abe T, Enjoji M, Kiyonari H, Kodama S, Fujioka S, Iwasaki K, Tsuboi Y
  • Journal Title: Neurosci Lett Volume: 764 Pages: 136234-136234
  • DOI: 10.1016/j.neulet.2021.136234
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DCTN1 Binds to TDP-43 and Regulates TDP-43 Aggregation (2021)
  • Author(s): Deshimaru M, Kinoshita-Kawada M, Kubota K, Watanabe T, Tanaka Y, Hirano S, Ishidate F, Hiramoto M, Ishikawa M, Uehara Y, Okano H, Hirose S, Fujioka S, Iwasaki K, Yuasa-Kawada J, Mishima T, Tsuboi Y
  • Journal Title: Int J Mol Sci Volume: 22 Issue: 8 Pages: 3985-3985
  • DOI: 10.3390/ijms22083985
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Meta-iodobenzylguanidine myocardial scintigraphy in Perry disease (2021)
  • Author(s): Mishima T, Fujioka S, Nishioka K, Li Y, Sato K, Houzen H, Yabe I, Shiomi K, Eriguchi M, Hara H, Hattori N, Tsuboi Y.
  • Journal Title: Parkinsonism and related disorders Volume: In press Pages: 49-53
  • DOI: 10.1016/j.parkreldis.2020.12.017
  • Peer Reviewed
• [Journal Article] A crucial role for Arf6 in the response of commissural axons to Slit. (2019)
  • Author(s): Kinoshita-Kawada M, Hasegawa H, Hongu T, Yanagi S, Kanaho Y, Masai I, Mishima T, Chen X, Tsuboi Y, Rao Y, Yuasa-Kawada J, Wu JY.
  • Journal Title: Development Volume: 146 Issue: 3 Pages: 1-9
  • DOI: 10.1242/dev.172106
  • NAID: 120007127965
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Perry disease: recent advances and perspectives (2019)
  • Author(s): Mishima T, Fujioka S, Tsuboi Y.
  • Journal Title: Expert Opinion on Orphan Drugs Volume: 7 Issue: 5 Pages: 253-259
  • DOI: 10.1080/21678707.2019.1625766
  • Peer Reviewed
• [Journal Article] Modeling Parkinson's Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells. (2018)
  • Author(s): Mishima T, Fujioka S, Fukae J, Yuasa-Kawada J, Tsuboi Y.
  • Journal Title: Int J Mol Sci. Volume: 19 Pages: 3870-3870
  • Peer Reviewed / Open Access
• [Presentation] Behavioral defects in a Dctn1 G71A knock-in mouse model of Perry disease (2021)
  • Author(s): 三嶋崇靖，弟子丸眞実，池田茉偉子，河田真理子，河田純一，藤岡伸助，窪田香織，渡辺拓也，清成寛，岩崎克典，坪井義夫
  • Organizer: 第15回パーキンソン病・運動障害疾患コングレス
• [Presentation] DCTN1 G71A変異Perry病ノックインマウスにおける黒質・線条体のtyrosine hydroxylase染色性低下 (2021)
  • Author(s): 三嶋崇靖
  • Organizer: 第14回パーキンソン病・運動障害疾患コングレス
• [Presentation] Characteristic of Perry disease in Japan (2020)
  • Author(s): 三嶋崇靖
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Perry病におけるMIBG心筋シンチグラフィー低下の頻度 (2019)
  • Author(s): 三嶋崇靖、藤岡伸助、坪井義夫
  • Organizer: 第13回パーキンソン病・運動障害疾患コングレス
• [Presentation] Perry症候群国際診断基準の確立 (2018)
  • Author(s): 三嶋崇靖、藤岡伸助、富山弘幸、矢部一郎、栗﨑玲一、藤井直樹、音成龍司、Ross OA、 Farrer MJ、Dickson DW、Wszolek ZK、服部信孝、坪井義夫
  • Organizer: 第59回日本神経学会
• [Presentation] DCTN1 G71A変異Perry症候群トランスジェニックマウスにおける行動障害 (2018)
  • Author(s): 三嶋崇靖、弟子丸眞実、渡辺拓也、窪田香織、河田真理子、河田純一、高崎浩太郎、上原吉就、神野尚三、岩崎克典、坪井義夫
  • Organizer: 第12回パーキンソン病・運動障害疾患コングレス
• [Presentation] Proposal of international diagnostic criteria and a new disease concept (2018)
  • Author(s): Takayasu Mishima, Fujioka S, Tomiyama H, Yabe I, Kurisaki R, Fujii N, Neshige R, Ross OA, Farrer MJ, Dickson DW, Wszolek ZK, Hattori N, Tsuboi Y
  • Organizer: International Congress of Parkinson’s Disease and Movement Disorders
  • Int'l Joint Research