Grant: Discovery Grants Program - Individual

For the past four decades, clinicians have developed a growing appreciation for the toll exacted by a group of lethal neurological disorders collectively called the peroxisome biogenesis disorders. All these diseases affect the assembly of the peroxisome, an intracellular organelle that is required for the degradation and biosynthesis of lipids. Therefore to understand the bases of the peroxisome biogenesis disorders, we must understand how peroxisomes are made in the cell. Until recently, one of the basic tenets of cellular organization was that the peroxisome constitutes a singular organellar compartment. All peroxisomes in any cell type or tissue were assumed to be identical in terms of their protein and lipid composition, their ability to import various proteins or transfer lipid species, and their metabolic capacity. The peroxisome was also believed to be an autonomous organelle that by itself maintained a balance of its chemical composition and functional status, being unable to communicate with other organelles via membrane-enclosed carriers. Peroxisome assembly was thus seen as a process by which structurally and functionally identical peroxisomes increase in size by the posttranslational import of all proteins at the same time and by the transfer of all membrane lipids in bulk. The resulting peroxisomal population, uniform in terms of its structural and functional properties, was believed to replicate by the fission or budding of fully assembled peroxisomes. Recent work from our laboratory has challenged this ""textbook"" view. We have shown that the peroxisome population of a cell consists of both large mature peroxisomes and smaller immature peroxisomes. The immature peroxisomes give rise to mature peroxisomes through the ordered and progressive conversion of a more immature form to a more mature form. The experiments that we now propose are aimed at elucidating the molecular mechanisms controlling this multistep peroxisome assembly pathway in regards to peroxisome formation and stepwise maturation. Full knowledge of how peroxisomes assemble is fundamental to understanding the molecular bases of the peroxisome biogenesis disorders and lays the foundation for future therapeutic approaches to the treatment of these diseases.