A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway

Yuichi Abe, Masanori Honsho, Ryoko Kawaguchi, Takashi Matsuzaki, Yayoi Ichiki, Masashi Fujitani, Kazushirou Fujiwara, Masaaki Hirokane, Masahide Oku, Yasuyoshi Sakai, Toshihide Yamashita, Yukio Fujiki

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Abstract

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.

Original languageEnglish
Pages (from-to)5321-5334
Number of pages14
JournalJournal of Biological Chemistry
Volume295
Issue number16
DOIs
Publication statusPublished - Apr 17 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Abe, Y., Honsho, M., Kawaguchi, R., Matsuzaki, T., Ichiki, Y., Fujitani, M., Fujiwara, K., Hirokane, M., Oku, M., Sakai, Y., Yamashita, T., & Fujiki, Y. (2020). A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway. Journal of Biological Chemistry, 295(16), 5321-5334. https://doi.org/10.1074/jbc.RA119.011989