title: Failure of microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance.
abstract: In contrast to peroxisomes in normal cells, remnant peroxisomes in cultured skin fibroblasts from a subset of the clinically severe peroxisomal disorders that includes the biogenesis disorder Zellweger syndrome and the single-enzyme defect D-bifunctional protein (D-BP) deficiency, are enlarged and significantly less abundant. We tested whether these features could be related to the known role of microtubules in peroxisome trafficking in mammalian cells. We found that remnant peroxisomes in fibroblasts from patients with PEX1-null Zellweger syndrome or D-BP deficiency exhibited clustering and loss of alignment along peripheral microtubules. Similar effects were observed for both cultured embryonic fibroblasts and brain neurons from a PEX13-null mouse with a Zellweger-syndrome-like phenotype, and a less-pronounced effect was observed for fibroblasts from an infantile Refsum patient who was homozygous for a milder PEX1 mutation. By contrast, such changes were not seen for patients with peroxisomal disorders characterized by normal peroxisome abundance and size. Stable overexpression of PEX11beta to induce peroxisome proliferation largely re-established the alignment of peroxisomal structures along peripheral microtubules in both PEX1-null and D-BP-deficient cells. In D-BP-deficient cells, peroxisome division was apparently driven to completion, as induced peroxisomal structures were similar to the spherical parental structures. By contrast, in PEX1-null cells the majority of induced peroxisomal structures were elongated and tubular. These structures were apparently blocked at the division step, despite having recruited DLP1, a protein necessary for peroxisome fission. These findings indicate that the increased size, reduced abundance, and disturbed cytoplasmic distribution of peroxisomal structures in PEX1-null and D-BP-deficient cells reflect defects at different stages in peroxisome proliferation and division, processes that require association of these structures with, and dispersal along, microtubules.
authors.affiliation: Cell Biology Group, Eskitis Institute for Cell and Molecular Therapies, Griffith University, 170 Kessels Road, Brisbane, Queensland 4111, Australia.
authors.forename: Tam
authors.initials: T
authors.lastname: Nguyen
authors.forename: Jonas
authors.initials: J
authors.lastname: Bjorkman
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Paton
authors.forename: Denis I
authors.initials: DI
authors.lastname: Crane
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000172:deficiency / Q000235:genetics; D000074183:ATPases Associated with Diverse Cellular Activities; D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement; D034281:Dynamins; D005347:Fibroblasts; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006836:Hydro-Lyases / Q000172:deficiency / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D018901:Peroxisomal Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D064029:Peroxisomal Multifunctional Protein-2; D020675:Peroxisomes / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D015211:Zellweger Syndrome / Q000378:metabolism / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; C490453:PEX11B protein, human; D015067:17-Hydroxysteroid Dehydrogenases; D020558:GTP Phosphohydrolases; D000074183:ATPases Associated with Diverse Cellular Activities; C111808:PEX1 protein, human; C110768:DNM1L protein, human; D034281:Dynamins; D006836:Hydro-Lyases; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human