Disturbance of brain environment by impairment of proteolysis leading to neurodegeneration

2015 Fiscal Year Final Research Report

• Project Area: Brain Environment
• Project/Area Number: 23111002
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: Takahashi Ryosuke 京都大学, 医学(系)研究科(研究院), 教授 (90216771)
• Co-Investigator(Kenkyū-buntansha): Urushitani Makoto 京都大学, 大学院医学研究科, 准教授 (60332326)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Keywords: ALS / Proteasome / Autophagy / Medaka / Gaucher disease / GBA / Lysosome / Alpha-synuclein

Outline of Final Research Achievements

We show that impairment of the ubiquitin-proteasome system, but not the autophagy-lysosome system in motor neurons replicates ALS in mice. Conditional knock-out mice of the proteasome subunit Rpt3 in a motor neuron-specific manner (Rpt3-CKO) showed locomotor dysfunction and typical ALS cytopathology. On the other hand, motor neuron-specific knock-out of Atg7 (Atg7-CKO), only resulted in no TDP-43 or FUS pathologies or motor dysfunction was observed. These results strongly suggest that proteasomes, but not autophagy, fundamentally govern the development of ALS. Recent genetic studies have revealed that GBA mutations confer a strong risk for sporadic Parkinson's disease (PD). To investigate how GBA mutations cause PD, we generated GBA knockout medaka that are deficient in glucocerebrosidase activity. Pathological findings represented lysosomal abnormalities in neurons and alpha-synuclein accumulation in axonal swellings, linking GBA mutation and pathogenesis of PD

Free Research Field

神経内科学