Molecular pathology of developing oligodendrocyte in a mouse model of Krabbe disease.

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K08313
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Institute for Developmental Research Aichi Developmental Disability Center
• 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)
• Project Period (FY): 2019-04-01 – 2023-03-31
• 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

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.

Free Research Field

Molecular neuropathology

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。