Impairment of cholesterol homeostasis cause a dysregulation of innate immune response, which might contribute to the pathogenesis of X-linked adrenoleukodystrophy

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08271
• 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: University of Toyama
• Principal Investigator: MORITA MASASHI 富山大学, 学術研究部薬学・和漢系, 准教授 (20191033)
• Co-Investigator(Kenkyū-buntansha): 宗 孝紀 富山大学, 学術研究部薬学・和漢系, 教授 (60294964)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 副腎白質ジストロフィー / ABCタンパク質 / ペルオキシソーム

Outline of Final Research Achievements

X-linked adrenoleukodystrophy is a rare genetic disorder caused by a mutation of ABCD1 gene which encode ABCD1 protein, a peroxisomal membrane protein. Dysfunction of ABCD1 cause abnormal accumulation of very long chain fatty acids in body fluids, especially in brain, which results in the inflammatory demyelination. However, VLCFA level is not related to the disease severity. The present studies show that impairment of cholesterol metabolisms was detected in ABCD1-deficient cells, which were associated with the enhancement of pro-inflammatory responses. These results suggest that disruption of cholesterol homeostasis due to the dysfunction of ABCD1 may contribute to pathogenesis of X-linked adrenoleukodystrophy.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

本疾患は男児2万人に一人の割合で起こるX連鎖劣性遺伝子疾患で、ABCD1遺伝子の変異により起こる難治性の炎症性脱髄疾患である。本疾患では発症機序が未解明のため、治療薬の開発が進んでいないのが現状である。本研究では、ABCD1タンパク質の機能を解析し、コレステロール代謝障害という新たな視点から発症機序の解明を行なった。この結果は、コレステロール代謝を標的とした本疾患の発症抑制薬開発に貢献できる。