Peroxisome Deficiency Impairs BDNF Signaling and Memory.

Yuichi Abe,Kaori Nakamura,Masanori Honsho,Toshihide Yamashita,Yukio Fujiki,Hiroshi Udo,Yoshiki Nishimura,Shigehiko Tamura

doi:10.3389/fcell.2020.567017

Abstract

Peroxisome is an intracellular organelle that functions in essential metabolic pathways including β-oxidation of very-long-chain fatty acids and biosynthesis of plasmalogens. Peroxisome biogenesis disorders (PBDs) manifest severe dysfunction in multiple organs including central nervous system (CNS), whilst the pathogenic mechanisms are largely unknown. We recently reported that peroxisome-deficient neural cells secrete an increased level of brain-derived neurotrophic factor (BDNF), resulting in the cerebellar malformation. Peroxisomal functions in adulthood brain have been little investigated. To induce the peroxisome deficiency in adulthood brain, we here established tamoxifen-inducible conditional Pex2-knockout mouse. Peroxisome deficiency in the conditional Pex2-knockout adult mouse brain induces the upregulated expression of BDNF and its inactive receptor TrkB-T1 in hippocampus, which notably results in memory disturbance. Our results suggest that peroxisome deficiency gives rise to the dysfunction of hippocampal circuit via the impaired BDNF signaling.

Highlights

Peroxisome is an essential subcellular organelle that plays a pivotal role in multiple metabolic pathways, including biosynthesis of ether-phospholipids, β-oxidation of very-long-chain fatty acids (VLCFA), and α-oxidation of branched-chain fatty acids (Wanders and Waterham, 2006)
brain-derived neurotrophic factor (BDNF) and TrkB-T1 were upregulated in the hippocampus of Pex2-KD mouse
These results suggest that the peroxisomal deficiency affects the hippocampal functions in adult mouse

Summary

Introduction

Peroxisome is an essential subcellular organelle that plays a pivotal role in multiple metabolic pathways, including biosynthesis of ether-phospholipids, β-oxidation of very-long-chain fatty acids (VLCFA), and α-oxidation of branched-chain fatty acids (Wanders and Waterham, 2006). PBDs are associated with mutations in PEX genes encoding peroxisome biogenesis factors, termed peroxins (Pex). Molecular mechanisms of peroxisome biogenesis have been investigated by several approaches including functional analyses of Pex proteins. Pex is a peroxisomal membrane protein containing RING (really interesting new gene) zinc finger at the C-terminal part (Tsukamoto et al, 1991; Fujiki et al, 2006). Pex and other peroxisomal RING proteins, Pex and Pex, form RING protein translocation complexes (Miyata and Fujiki, 2005; Okumoto et al, 2014) functioning as the E3 ubiquitin ligase for Pex, the receptor for the proteins harboring peroxisomal targeting signals (PTS) (Fujiki et al, 2006). Deficiency of Pex results in typical import defects of peroxisomal matrix proteins (Tsukamoto et al, 1991; Shimozawa et al, 1992)

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Results

Conclusion