PEX13 Mutant Mice as Models of Zellweger Syndrome Neuropathogenesis and Peroxisomal Matrix Protein Import

Abstract

Peroxisomes are essential for the developing brain as the loss of functional peroxisomes leads to mild to severe Peroxisome Biogenesis Disorders (PBD) with significant neurological involvement. Zellweger Syndrome (ZS) represents the most severe form of PBDs resulting from a mutation in PEX genes, including PEX13, which encode peroxins necessary for peroxisome biogenesis. ZS patients exhibit a range of clinical abnormalities including hypotonia, multi-organ failure, abnormal metabolic profile with significant neuropathologies and death within a year after birth. As mutation in Pex13 in humans result in ZS, animal models with ubiquitous and targeted disruption of PEX13 were generated in order to understand the unifying molecular pathogenesis of ZS. PEX13 knockout (KO) and brain specific disruption of PEX13 mice (referred as PEX13 brain mutant) were developed in our laboratory and applied as experimental tools previously and in this thesis, to explore the molecular and cellular basis of ZS neuropathology. The PEX13 KO mice, exhibits severe ZS phenotype which includes hypotonia, neuronal migration defect, impaired fatty acid oxidation and plasmalogen synthesis, and early neonatal death.