Peroxisome biogenesis and human disorders
Professor Yukio FUJIKI, University of Hyogo, Hyogo; Kyushu University, Fukuoka, Japan
Peroxisome, an intracellular organelle, functions in various metabolic pathways, including-oxidation of very long chain fatty acids, synthesis of ether-lipids such as plasmalogens, and H2O2 metabolism. The functional consequence of human peroxisomes is represented by fatal genetic peroxisome biogenesis disorders (PBD) such as Zellweger syndrome (ZS). We successfully isolated a dozen PEX genes encoding peroxisome biogenesis factors termed peroxins, including the first Zellweger gene PEX2 (Nature, 1991; Science, 1992). Fourteen peroxins have been identified in peroxisome biogenesis in mammals. By making use of another peroxisome-deficient Chinese hamster ovary (CHO) cell mutant ZP114, we recently found that the pro-apoptotic Bcl2 protein BAK regulates peroxisome membrane permeability and catalase export. I will also address mechanisms underlying the regulation of peroxisome protein import and membrane assembly. Next, to investigate mechanisms underlying pathogenesis of PBD, we established and analyzed a new PBD model mouse defective in Pex14, termed Pex14ΔC/ΔC mouse. Pex14ΔC/ΔC mouse manifests severe brain abnormality such as impaired dendritic development of Purkinje cells in cerebellum. The results suggest for the first time that dysregulation of the BDNF-TrkB pathway, an essential signaling for cerebellar morphogenesis, gives rise to the pathogenesis of cerebellum in PBDs.
Peroxisome, peroxisomal protein import, peroxisome biogenesis disorders (PBD), peroxins, PBD model mouse, PBD pathogenesis