Proposal of a new mechanism of Krabbe disease to replace the 'psychosine hypothesis'

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15892
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Watanabe Takashi 川崎医科大学, 医学部, 助教 (60817071)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: クラッベ病 / サイコシン仮説 / ガラクトシルセラミド

Outline of Final Research Achievements

Krabbe disease, also known as globoid cell leukodystrophy, is caused by the genetic deficiency of lysosomal enzyme galactosylceramide (GalCer) β-galactosidase (GALC). The pathogenesis of Krabbe disease has long been explained by the 'psychosine hypothesis', in which death of oligodendrocyte and Schwann cell due to psychosine accumulation causes demyelination and neuroinflammation in both the CNS and PNS.
We clarified that psychosine is produced by the deacylated of GalCer by ACDase with the assistance of saposin-D and the despite of little accumulation of psychosine in the mouse model of Krabbe disease, demyelination was not significantly improved especially in the PNS. These findings indicate that the pathophysiology of Krabbe disease cannot be explained by the 'psychosine hypothesis' alone.

Free Research Field

ライソゾーム病

Academic Significance and Societal Importance of the Research Achievements

クラッベ病はGalCer β-ガラクトシダーゼ (GALC)の遺伝的変異による先天性の脱髄疾患であるが、そのメカニズムは未だ不明な点が多い。本研究において、サイコシンを蓄積しないTwi/Sap-D KOマウスにおいて、特に末梢神経の脱髄病変が改善しなかったことから、クラッベ病の神経病態はサイコシンの蓄積だけでは説明できず、GalCerによるGALC欠損マクロファージ/ミクログリアの活性化に起因する神経炎症が重要な役割を果たしている可能性が示唆される。このように、クラッベ病の病態理解は今後の治療法開発において重要な意義がある。