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

Yuji Kurihara, Kotone Mitsunari, Nagi Mukae, Hirotaka Shoji, Tsuyoshi Miyakawa, Michiko Shirane

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number11
JournalMolecular brain
Volume16
Issue number1
DOIs
Publication statusPublished - 12-2023

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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