PDZD8-deficient mice manifest behavioral abnormalities related to emotion, cognition, and adaptation due to dyslipidemia in the brain

Molecular Brain

Research

Yuji Kurihara¹  Kotone Mitsunari¹  Michiko Shirane¹  Nagi Mukae¹  Hirotaka Shoji²  Tsuyoshi Miyakawa² 

[1] Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan;Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Aichi, Japan;

关键词: PDZD8;    Knockout mouse;    Behavior;    Dyslipidemia;    Lipophagy;    Cholesterol;   

DOI  :  10.1186/s13041-023-01002-4

 received in 2022-12-29, accepted in 2023-01-12,  发布年份 2023

来源: Springer

【 摘 要 】

Although dyslipidemia in the brain has been implicated in neurodegenerative disorders, the molecular mechanisms underlying its pathogenesis have been largely unclear. PDZD8 is a lipid transfer protein and mice deficient in PDZD8 (PDZD8-KO mice) manifest abnormal accumulation of cholesteryl esters (CEs) in the brain due to impaired lipophagy, the degradation system of lipid droplets. Here we show the detailed mechanism of PDZD8-dependent lipophagy. PDZD8 transports cholesterol to lipid droplets (LDs), and eventually promotes fusion of LDs and lysosomes. In addition, PDZD8-KO mice exhibit growth retardation, hyperactivity, reduced anxiety and fear, increased sensorimotor gating, and impaired cued fear conditioned memory and working memory. These results indicate that abnormal CE accumulation in the brain caused by PDZD8 deficiency affects emotion, cognition and adaptive behavior, and that PDZD8 plays an important role in the maintenance of brain function through lipid metabolism.

【 授权许可】

CC BY   
© The Author(s) 2023

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