Impaired neurogenesis and associated gliosis in mouse brain with PEX13 deficiency.

Zellweger syndrome (ZS), a neonatal lethal disorder arising from defective peroxisome biogenesis, features profound neuroanatomical abnormalities and brain dysfunction. Here we used mice with brain-restricted inactivation of the peroxisome biogenesis gene PEX13 to model the pathophysiological features of ZS, and determine the impact of peroxisome dysfunction on neurogenesis and cell maturation in ZS. In the embryonic and postnatal PEX13 mutant brain, we demonstrate key regions with altered brain anatomy, including enlarged lateral ventricles and aberrant cortical, hippocampal and hypothalamic organization. To characterize the underlying mechanisms, we show a significant reduction in proliferation, migration, differentiation, and maturation of neural progenitors in embryonic E12.5 through to P3 animals. An increasing reactive gliosis in the PEX13 mutant brain started at E14.5 in association with the pathology. Together with impaired neurogenesis and associated gliosis, our data demonstrate increased cell death contributing to the hallmark brain anatomy of ZS. We provide unique data where impaired neurogenesis and migration are shown as critical events underlying the neuropathology and altered brain function of mice with peroxisome deficiency.

Mitochondrial changes and oxidative stress in a mouse model of Zellweger syndrome neuropathogenesis.

Zellweger syndrome (ZS) is a peroxisome biogenesis disorder that involves significant neuropathology, the molecular basis of which is still poorly understood. Using a mouse model of ZS with brain-restricted deficiency of the peroxisome biogenesis protein PEX13, we demonstrated an expanded and morphologically modified brain mitochondrial population. Cultured fibroblasts from PEX13-deficient mouse embryo displayed similar changes, as well as increased levels of mitochondrial superoxide and membrane depolarization; this phenotype was rescued by antioxidant treatment. Significant oxidative damage to neurons in brain was indicated by products of lipid and DNA oxidation. Similar overall changes were observed for glial cells. In toto, these findings suggest that mitochondrial oxidative stress and aberrant mitochondrial dynamics are associated with the neuropathology arising from PEX13 deficiency.