Neuropathology in a Mouse Model of Zellweger Syndrome

Abstract

Zellweger syndrome (ZS) is a congenital peroxisome biogenesis disorder which has both features of neurodegeneration and defective neurodevelopment. ZS patients exhibit significant changes to brain morphology, prominent cell migration defects, and neurodegeneration; defects leading to severe motor and cognitive dysfunction. ZS is caused by mutation in PEX genes which encode proteins necessary for peroxisomes biogenesis. Loss of peroxisome biogenesis results in the deficiency of various peroxisomal metabolic functions, such as [beta]-oxidation of very-long-chain-fatty acids, and biosynthesis of essential compounds that include bile acids, plasmalogens and docosahexaenoic acid. Despite these important findings, the molecular basis of ZS neuropathology is still unknown. For this study, which comprised a focus on the mechanisms/pathways involved in ZS neuropathology, mice with brain restricted deletion of the PEX13 gene were used as an animal model of ZS neuropathogenesis. PEX13 is required for the import of newly synthesized proteins into the peroxisome matrix. PEX13 brain mutant mice display characteristics typical of a milder ZS phenotype, including extended survival rate, and are therefore an appropriate model to stud neurodevelopmental changes at both early and postnatal developmental stages.