Metabolic abnormality and pathogenesis of peroxisome biogenesis deficiency

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07386
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kyushu University
• Principal Investigator: Abe Yuichi 九州大学, 基幹教育院, 学術研究員 (00529092)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ペルオキシソーム / BDNF / 海馬 / 還元化

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. We previously reported that an elevated level of brain-derived neurotrophic factor (BDNF) together with the enhanced expression of TrkB-T1, resulting in anormal development of Purkinje cells. In this research, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion.
Peroxisomal functions in adulthood brain have been little investigated. To induce the peroxisome deficiency in adulthood brain, we established tamoxifen-inducible conditional Pex2-knockout mouse. Peroxisome deficiency in the conditional Pex2-knockout adult mouse brain induces the upregulated expression of BDNF and its inactive receptor TrkB-T1 in hippocampus, which notably results in memory disturbance.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

ペルオキシソーム形成異常症に関して、我々はBDNF-TrkBシグナル伝達系異常を介した小脳形態障害の分子機構を世界で初めて解明してきた。本研究成果は、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BDNF発現異常を明らかにし、未解明であったペルオキシソーム形成異常症の病態発症機構において、代謝障害を起因とする中枢神経系障害の分子機構を明らかにした重要な知見である。さらに、ペルオキシソーム機能が成体マウス海馬における記憶形成に必須であることを示し、成体脳における新たなペルオキシソーム機能を明らかにした重要な知見である。