Adrenoleukodystrophy: effect of bone marrow transplantation in abcd1-deficient mouse

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09961
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: University of Toyama
• Principal Investigator: MORITA MASASHI 富山大学, 大学院医学薬学研究部(薬学), 准教授 (20191033)
• Co-Investigator(Kenkyū-buntansha): 長井 良憲 富山県立大学, 工学部, 教授 (30431761)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 副腎白質ジストロフィー / 神経変性疾患 / ペルオキシソーム / 骨髄移植 / ABCタンパク質 / ミクログリア

Outline of Final Research Achievements

X-linked adrenoleukodystrophy patients display cerebral inflammatory demyelination. Although very long chain fatty acids (VLCFA) accumulation is thought to be the main culprit underlying the pathogenesis, the mechanisms by which the VLCFA causes demyelinating neurodegeneration have not yet been elucidated. At present, bone marrow transplantation (BMT) is effective in halting disease progression. In our BMT experiments, the VLCFA plasma level significantly decreased and donor-derived bone marrow cells (BMDM) were engrafted in the brain as macrophage-like cells. However, the VLCFA levels in recipient mouse brain was not reduced by BMT. In the recipient mouse brain, some cholesterol metabolism-related genes were changed by BMT. These results suggest that BMDMs may interact with resident glial cells or endothelial cells, and thus may attenuate the cholesterol metabolic abnormality, which in turn suppresses neuroinflammation.

Free Research Field

生化学、細胞生物学

Academic Significance and Societal Importance of the Research Achievements

副腎白質ジストロフィーは発病メカニズムが明らかになっていない遺伝性の神経変性疾患で、日本でも毎年新生児約20人程度の割合で患者がいると推定され、治療薬開発は僅々の重要課題である。本研究では、本疾患がペルオキシソーム機能欠損による極長鎖脂肪酸代謝異常とともに、コレステロール代謝異常が発病に関わっている可能性を明らかにした。将来的にはコレステロール代謝異常を標的とした炎症性脱随を予防するという新しい視点から本疾患の発病抑制薬の開発が期待される。