PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy
Keiko Morita,
Mariko Wada,
Kohta Nakatani,
Yuki Matsumoto,
Nahoki Hayashi,
Ikuko Yamahata,
Kotone Mitsunari,
Nagi Mukae,
Masatomo Takahashi,
Yoshihiro Izumi,
Takeshi Bamba,
Michiko Shirane
Affiliations
Keiko Morita
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan
Mariko Wada
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan
Kohta Nakatani
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
Yuki Matsumoto
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan
Nahoki Hayashi
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan
Ikuko Yamahata
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan
Kotone Mitsunari
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan
Nagi Mukae
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan
Masatomo Takahashi
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
Yoshihiro Izumi
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
Takeshi Bamba
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
Michiko Shirane
Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan; Corresponding author
Summary: Dyslipidemia including the accumulation of cholesteryl esters (CEs) in the brain is associated with neurological disorders, although the underlying mechanism has been unclear. PDZD8, a Rab7 effector protein, transfers lipids between endoplasmic reticulum (ER) and Rab7-positive organelles and thereby promotes endolysosome maturation and contributes to the maintenance of neuronal integrity. Here we show that CEs accumulate in the brain of PDZD8-deficient mice as a result of impaired lipophagy. This CE accumulation was not affected by diet, implicating a defect in intracellular lipid metabolism. Whereas cholesterol synthesis appeared normal, degradation of lipid droplets (LDs) was defective, in the brain of PDZD8-deficient mice. PDZD8 may mediate the exchange of cholesterol and phosphatidylserine between ER and Rab7-positive organelles to promote the fusion of CE-containing LDs with lysosomes for their degradation. Our results thus suggest that PDZD8 promotes clearance of CEs from the brain by lipophagy, with this role of PDZD8 likely contributing to brain function.
