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

  • Author / Creator
    Mast, Fred D
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
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    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Lehner, Richard (Pediatrics)
    • Nabi, I Robert (Cellular and Physiological Sciences, University of British Columbia)
    • Dacks, Joel B (Cell Biology)
    • Holmes, Charles FB (Biochemistry)
    • Simmen, Thomas (Cell Biology)