Investigation of novel cellular function of Progranulin and its molecular mechanism

• Project/Area Number: 16K08557
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Tokyo Medical University
• Principal Investigator: Kusakari Shinya 東京医科大学, 医学部, 助教 (10510901)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 神経変性疾患 / 神経細胞死 / シグナル伝達 / 神経科学 / 脳神経疾患

Outline of Final Research Achievements

Dysfunction of Progranulin by gene mutation is thought to cause Frontotemporal dementia. However, its molecular mechanism is still not well understood, and the progranulin receptor involved in the onset is also unknown. In this study, I attempted to identify Pogranulin receptors and binding molecules involved in the onset of FTD, and found some novel binding partners. Furthermore, interaction with Progranulin induced lysosomal degradation of these binding molecules. These results suggest that Progranulin may be involved in neuroprotective function control via these new binding molecules.

Academic Significance and Societal Importance of the Research Achievements

前頭側頭型認知症（FTD）をはじめとする神経変性疾患において、これまでに研究により複数の原因遺伝子が同定されているが、その発症メカニズムには未だ不明な点が多く残されている。このため、本研究で同定したProgranuliin結合分子は、発症メカニズム解明の一助となることが期待される。また、Progranulinは、近年、FTDだけでなくアルツハイマー病（AD）やパーキンソン病（PD）の発症にも関わると報告されており、本研究成果はFTDのみならず、ADやPDなどの神経変性疾患の根本的治療法および治療薬の開発の基盤となることが予想される。

Research Products

• [Journal Article] Calmodulin-like skin protein protects against spatial learning impairment in a mouse model of Alzheimer disease (2018)
  • Author(s): Shinya Kusakari, Mikiro Nawa, Katsuko Sudo, Masaaki Matsuoka
  • Journal Title: Journal of neurochemistry Volume: 144 Issue: 2 Pages: 218233-218233
  • DOI: 10.1111/jnc.14258
  • Peer Reviewed
• [Journal Article] An Alzheimer's disease-linked rare mutation potentiates netrin receptor uncoordinated-5C-induced signaling that merges with amyloid β precursor protein signaling. (2016)
  • Author(s): Hashimoto Y, Toyama Y, Kusakari S, Nawa M, Matsuoka M.
  • Journal Title: J Biol Chem. Volume: N/A Issue: 23 Pages: 1228212293-1228212293
  • DOI: 10.1074/jbc.m115.698092
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Analysis of molecular mechanism underlying cell death induced by an ALS/FTD-causative gene CHCHD10, S59L-CHCHD10 (2019)
  • Author(s): 小林悠里、草苅伸也、鈴木宏昌、松岡正明
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Calmodulin-like skin proteinはアルツハイマー病モデルマウスの空間学習障害を抑制する (2019)
  • Author(s): 草苅伸也、名和幹朗、須藤カツ子、松岡正明
  • Organizer: 第28回神経行動薬理若手研究者の集い
• [Presentation] Calmodulin-like skin proteinはアルツハイマー病モデルマウスの空間学習障害を (2017)
  • Author(s): 草苅伸也、名和幹朗、須藤カツ子、松岡正明
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール
  • Year and Date: 2017-03-15
• [Presentation] The impact of ion dynamics on tyrosine phosphorylation of SIRPα (2017)
  • Author(s): Daiki Jingu, Mika Iino, Shinya Kusakari, Miho Hashimoto, Hiroshi Ohnishi
  • Organizer: 日本プロテインホスファターゼ研究会学術集会
• [Presentation] Calmodulin-like skin protein prevents spatial learning impairment of Alzheimer’s disease model mice (2016)
  • Author(s): Shinya Kusakari, Mikiro Nawa, Katsuko Sudo, Masaaki Matsuoka
  • Organizer: Society for Neuroscience 46th Annual Meeting 2016
  • Place of Presentation: San Diego, Convention Center
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice (2016)
  • Author(s): Shinya Kusakari, Fumihito Saitow, Miho Sato-Hashimoto, Yasunori Matsuzaki, Takenori Kotani, Yoji Murata, Hirokazu Hirai, Hidenori Suzuki, Takashi Matozaki, Hiroshi Ohnishi
  • Organizer: 12th International Conference on Protein Phosphatase Protein Phosphatases in Health and Diseases
  • Place of Presentation: 近畿大学
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Remarks] 東京医科大学薬理学分野ホームページ
  • URL: http://www.tokyo-med.ac.jp/pharmacol/top.html
• [Remarks] 東京医科大学薬理学分野ホームページ
  • URL: http://www.tokyo-med.ac.jp/pharmacol/