Defect of peroxisome metabolism impairs development of central nervous system

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15621
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Kyushu University
• Principal Investigator: Abe Yuichi 九州大学, 生体防御医学研究所, 学術研究員 (00529092)
• Research Collaborator: Fujiki Yukio ; Honsho Masanori ; Yamashita Toshihide ; Ohgi Ryohei
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: ペルオキシソーム / ペルオキシソーム形成異常症 / 小脳 / プルキンエ細胞

Outline of Final Research Achievements

Peroxisome is a subcellular organelle essential for various metabolic reactions. Peroxisome biogenesis disorders (PBDs) manifest as neurological deficits in the brain, including abnormal cerebellum development. However, the mechanisms underlying pathogenesis remain enigmatic. In this research, we showed that ERK and AKT signaling are attenuated in peroxisome-deficient mouse by an elevated level of brain-derived neurotrophic factor (BDNF) together with the enhanced expression of TrkB-T1, a dominant-negative isoform of the BDNF receptor. This result suggests that dysregulation of the BDNF-TrkB pathway, an essential signaling for cerebellar morphogenesis, gives rise to the pathogenesis of cerebellum in PBDs. In addition, we revealed that the elevation of BDNF was induced by the cytosolic reductive state caused by the mislocalized catalase in peroxisome-deficient glia cells. Thus, our findings demonstrate for the first time the pathogenesis of PBDs.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

これまで、ペルオキシソーム形成異常症の病態発症機構に関して、分子レベルでの解明には至っていなかった。そんななか、我々の研究成果はBDNF-TrkBシグナル伝達系の異常が小脳形態異常の原因の一つであることを示し、世界で初めてペルオキシソーム形成異常症の病態発症機構を分子レベルで解明することに漕ぎ着けた。さらに、ペルオキシソーム欠損により誘発される細胞質還元化が及ぼす細胞機能への影響に関しても世界で初めての発見である。これらの成果は根本的な治療法が確立されていないペルオキシソーム形成異常症の治療法開発に繋がる可能性が高い。