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Permanent link (DOI): https://doi.org/10.7939/R3DV1D011

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A comprehensive assessment of peroxisome biology: ER-dependent peroxisome proliferation control, evolution of organelle inheritance in yeast and a Drosophila model system of Zellweger syndrome Open Access

Descriptions

Other title
Subject/Keyword
peroxisome proliferation
reticulon
evolution
peroxisomes
organelle inheritance
peroxin
Zellweger syndrome
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Mast, Fred D
Supervisor and department
Rachubinski, Richard A (Cell Biology)
Examining committee member and department
Lehner, Richard (Pediatrics)
Simmen, Thomas (Cell Biology)
Holmes, Charles FB (Biochemistry)
Dacks, Joel B (Cell Biology)
Nabi, I Robert (Cellular and Physiological Sciences, University of British Columbia)
Department
Department of Cell Biology
Specialization

Date accepted
2013-08-26T14:40:58Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
The modern eukaryotic cell is a meshwork of encapsulating membranes that compartmentalize many distinct biochemical processes. It is complex. This complexity facilitates the many unique and diverse processes that aid the eukaryote in its growth, division and adaptation to its environment. A comprehensive understanding of this complexity is benefited by the integration of knowledge from cell biological and molecular mechanisms, from the evolution of the factors involved in these processes and from studying how these mechanisms in cells are integrated into tissues and organisms. This thesis attempts to achieve this for a particular organelle, the peroxisome. We studied the mechanisms of peroxisome biogenesis and proliferation in the yeast Saccharomyces cerevisiae. We found that peroxisome proliferation takes cues from the growth cycle of the cell and that the endoplasmic reticulum is involved in regulating this process. Searching deeper, we discovered the presence of a reticulon-peroxin complex composed of Pex30p, Pex29p, Rtn1p and Yop1p that regulates peroxisome proliferation from the endoplasmic reticulum. We identified homologs of one of the complex members, Pex30p, in metazoans and implicate the involvement of the Drosophila homolog of Pex30p, DmelPex23, in regulating peroxisome proliferation. We next addressed the evolutionary question of how adaptability is generated in a system composed of interacting cellular machineries, each with a separate and functionally critical job to perform. Using the machinery for organelle inheritance mechanisms present in budding yeasts as a model system we propose an evolutionary model whereby the emergence of myosin V–based organelle inheritance results from mechanisms of paralogy, mutation, and the appearance of pliable evolutionarily novel adaptor proteins. We also demonstrate the relevance of Drosophila as a genetic model for early developmental defects associated with human peroxisome biogenesis disorders. Mutation of the PEX1 gene is the most common cause of peroxisome biogenesis disorders and is one of the causes of the most severe form of the disorders, Zellweger syndrome. Inherited mutations in Drosophila Pex1 correlate with reproducible defects during early development. A microarray analysis defined several clusters of genes whose expression varied significantly between wild-type and mutant larvae, implicating peroxisomal function in neuronal development, innate immunity, lipid and protein metabolism, gamete formation, and meiosis.
Language
English
DOI
doi:10.7939/R3DV1D011
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Mast, F.D., A. Fagarasanu, B. Knoblach, and R.A. Rachubinski. 2010. Peroxisome biogenesis: something old, something new, something borrowed. Physiology. 25:347–356. doi:10.1152/physiol.00025.2010.Mast, F.D., R.A. Rachubinski and J.B.Dacks. 2013. Emergent complexity in myosin V-based organelle inheritance. Mol Biol Evo. 29:975–984. doi:10.1093/molbev/msr264.Mast, F. D., Li, J., Virk, M. K., Hughes, S. C., Simmonds, A. J., & Rachubinski, R. A. 2011. A Drosophila model for the Zellweger spectrum of peroxisome biogenesis disorders. Dis Mod Mech. 4:659-672. doi:10.1242/dmm.007419Mast, F. D., Fagarasanu, A., & Rachubinski, R. A. (2010). The peroxisomal protein importomer: a bunch of transients with expanding waistlines. Nature cell biology, 12(3), 203–205. doi:10.1038/ncb0310-203Fagarasanu, A., Mast, F. D., Knoblach, B., & Rachubinski, R. A. (2010). Molecular mechanisms of organelle inheritance: lessons from peroxisomes in yeast. Nature Reviews Molecular Cell Biology, 11(9), 644–654. doi:10.1038/nrm2960Perry, R. J., Mast, F. D., & Rachubinski, R. A. (2009). Endoplasmic reticulum-associated secretory proteins Sec20p, Sec39p, and Dsl1p are involved in peroxisome biogenesis. Eukaryotic cell, 8(6), 830–843. doi:10.1128/EC.00024-09

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