Grant: Foundation Grant

Drosophila; Genetic Diseases; Model Organisms Of Human Disease; Organelles; Peroxisome; Peroxisome Biogenesis Disorders; Rare Diseases; Small Molecule Therapeutics; Yeast

<html> <body> <p>Peroxisomes are membrane-bound organelles found in organisms from yeasts to mammals and in most cell<br> types. They perform diverse metabolic reactions, primarily in lipid metabolism and detoxification of<br> activated oxygen species.<br> <br> Peroxisomes are essential for human survival, a fact underscored by the existence of a number of inherited<br> disorders, collectively called the peroxisome biogenesis disorders (PBDs), resulting from dysfunction of<br> peroxisome biogenesis. The PBDs include Zellweger syndrome, neonatal adrenoleukodystrophy, infantile<br> Refsum disease, and rhizomelic chondrodysplasia punctata. These autosomal recessive disorders are caused<br> by gene mutations that impair peroxisome biogenesis. Because of the diverse roles of peroxisomes, the<br> symptoms of PBDs are&nbsp;diverse, including abnormal lipid metabolism, mental retardation, renal and<br> hepatic dysfunction, craniofacial abnormalities and hypotonia. PBDs are usually fatal early in infancy.<br> We have been elucidating the mechanisms of peroxisome biogenesis to better understand the molecular<br> bases of the PBDs. We have defined where and how peroxisomes are made in cells, characterized many<br> <em>PEX</em> genes required for peroxisome biogenesis whose mutation causes the PBDs, elucidated how<br> peroxisomes are inherited by cells, and developed an insect model of the PBDs that allows rapid screening<br> of potential therapeutics for the PBDs.<br> <br> We use yeast, fruit fly and mouse as model organisms to understand the molecular bases of the PBDs. We<br> combine classical cell biology methodologies like electron microscopy and subcellular fractionation with<br> genetics, biochemistry, molecular biology and advanced confocal and video microscopy to achieve a<br> mechanistic understanding of peroxisome assembly and of how assembly goes awry in the PBDs.<br> Knowledge of the genes and pathways involved in peroxisome biogenesis and of the dysfunctionality in<br> these systems that results in the clinical manifestations of the PBDs have now provided for an initial<br> therapeutic treatment for these diseases. With Andrew Simmonds (University of Alberta) and Nancy<br> Braverman (McGill University), we have begun a clinical trial using a chemical chaperone to facilitate folding<br> of a poorly folded mutant PEX protein that causes Zellweger syndrome in a subset of patients.<br> <br>Along with our clinically oriented studies, we continue to define the basic mechanisms of peroxisome<br> biogenesis. The central question in peroxisome biogenesis today relates to the origin of peroxisomes in the<br> cell. Over many years we provided evidence that incontrovertibly showed that new peroxisomes form from<br> the cell&rsquo;s endoplasmic reticulum (ER), the entry to the secretory pathway. Using systems-level proteomic,<br> transcriptomic and microscopic assays done in collaboration with John Aitchison at the Seattle Biomedical Research Institute, we are now determining the roles of ER-resident proteins in forming preperoxisomal<br> vesicles, defining how these vesicles are scissioned from the ER and elucidating how <em>de novo</em> peroxisome<br> biogenesis coordinates with peroxisome division and inheritance to regulate a cell&rsquo;s peroxisome population.<br> <br>Our research into the fundamentals of peroxisome biology has now translated into patient treatment, thus<br> fulfilling the premise and promise of basic health research in providing not only discoveries of how a basic<br> cellular process functions but also a molecular foundation for the mechanistic understanding of a disease<br> and provision for its rationalized treatment.</p> </body> </html>