ニーマン・ピック病C型におけるセラミドキナーゼの関与と治療標的としての検討

抄録

(Background and purpose)

Niemann-Pick disease type C (NPC) is a genetic disorder in which patient cells have endosomal/lysosomal accumulation of cholesterol.  No approved drug improves cholesterol accumulation, and the creation of new therapeutic drugs are desired. Currently, there are many relationships between sphingolipids and NPC have been reported. This study investigated the relationship between NPC and ceramide-1-phosphate, produced by phosphorylating ceramide, using NPC1-null mice.

(Results and discussion)

NPC is characterized by clinically affecting the brain and liver; premature death invariably results.

We generated double-knockout (DKO) mice lacking NPC1 and CerK and compared the phenotypes of NPC mice and DKO mice in these tissues. In the brain, cholesterol accumulation and Purkinje cell survival were improved in DKO mice compared with those in NPC1-null mice. In the liver, cholesterol accumulation and liver disorder were improved in DKO mice compared with those in NPC1-null mice. Administration of a CerK inhibitor to NPC1-null mice delayed the onset of clinical signs and prolonged the lifespan. These results suggest that CerK may be helpful as a novel therapeutic target for NPC.