Molecular pathology of developing oligodendrocyte in a mouse model of Krabbe disease.
| Project/Area Number |
19K08313
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Institute for Developmental Research Aichi Developmental Disability Center |
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Principal Investigator |
Enokido Yasushi 愛知県医療療育総合センター発達障害研究所, 細胞病態研究部, 室長 (90263326)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | クラッベ病 / オリゴデンドロサイト / ミエリン / 脱髄 / マイクロRNA / ライソゾーム病 / 脂質異常症 / miR-219 / スフィンゴ糖脂質 / リソソーム / スフィンゴリピドーシス / Akt / 糖脂質 |
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| Outline of Research at the Start |
最近我々が明らかにした、KDの疾患モデルマウス（Twitcherマウス）で認められるOLの発達異常とサイコシンの異常蓄積（Inamura et al., Neurobiol Dis 2018）に着目し、それらに対するAkt/mTORシグナルやマイクロRNAの関与、ならびに未知の細胞内サイコシン産生経路の存否について解析を行う。得られた知見をもとに、KDの新たな治療法開発をめざす。
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| Outline of Final Research Achievements |
Krabbe disease (KD) is an inherited demyelinating disease caused by the deficiency of galactosylceramidase activity. Most of the patients are characterized by early-onset cerebral demyelination with oligodendrocyte (OL) death.
By using twitcher mice, an authentic mouse model of KD, we have demonstrated that KD OLs exhibit cell-autonomous developmental defects and undergo apoptotic death associated with the aberrant accumulation of endogenous psychosine. In the present study, we further investigated the role of miR-219 in the cellular pathogenesis of twitcher mouse OLs. We found that expression and functional activity of miR-219 were repressed in developing twitcher mouse OLs. We also found that exogenously supplemented miR-219 rescued their developmental defects and apoptotic death. miR-219 also reduced endogenous accumulation of psychosine in twitcher OLs.
Our findings provide new insights into the role of miR-219 for the treatment of OL pathologies in KD.
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| Academic Significance and Societal Importance of the Research Achievements |
クラッベ病の主徴とされるオリゴデンドロサイトの変性脱落ならびに細胞内サイコシン産生経路の分子メカニズムは、これまで大きな謎とされてきた。本研究で明らかとなった「クラッベ病におけるmiR-219の機能不全とその病態改善効果」は、本疾患の発症機構の理解にとどまらず、オリゴデンドロサイトの分化・成熟異常を伴う他の小児脱髄疾患や神経発達障害の新たな治療法開発にもつながる可能性を持つことから、本研究成果は学術的独自性と創造性の双方を備えたものと考えられる。
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Report
(5 results)
Research Products
(7 results)
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[Journal Article] R3HDM1 haploinsufficiency is associated with mild intellectual disability.2021
Author(s)
Fukushi D, Inaba M, Katoh K, Suzuki Y, Enokido Y, Nomura N, Tokita Y, Hayashi S, Mizuno S, Yamada K, Wakamatsu N
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Journal Title
Am J Med Genet A
Volume: 185
Issue: 6
Pages: 1776-1786
DOI
Related Report
Peer Reviewed
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