Molecular bases of selective vulnerability of motor neurons in amyotrophic lateral sclerosis

Research Project

Project/Area Number	15K15081
Research Category	Grant-in-Aid for Challenging Exploratory Research
Allocation Type	Multi-year Fund
Research Field	Pathological medical chemistry
Research Institution	Kyoto University
Principal Investigator	Tanabe Yasuto 京都大学, 医学研究科, 客員研究員 (10311309)
Project Period (FY)	2015-04-01 – 2018-03-31
Project Status	Completed (Fiscal Year 2017)
Budget Amount *help	¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000) Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000) Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords	神経変性疾患 / 筋萎縮性側索硬化症 / 運動ニューロン / 運動ニューロン病
Outline of Final Research Achievements	Neurodegenerative diseases can be characterized by their unique distinct set of neuronal subtypes that exhibit progressive and selective vulnerability. In ALS, progressive and selective degeneration with the accumulation of pathological aggregates, including TDP-43, is observed in motor neurons (MNs), especially those that innervate fast muscles (FF-MN) in the spinal cord. Our study using cultured cells in vitro showed that Notch signals involved in the specification of FF-MN appeared to be also involved in the acquisition of vulnerability against TDP-43 full-length protein expression and resulted in the formation TDP-43 aggregates mostly located within the nucleus.　Although we were not able to show cytoplasmic re-distribution of TDP-43 aggregates even in the presence of a proteasome inhibitor, our results may add to the emerging view that nuclear TDP-43 proteinopathy may take place prior to the onset of cytoplasmic event and underlie the selective vulnerability of MNs in ALS.