TRANSLATIONAL IMPACT

Abstract

Zellweger syndrome (ZS) is an incurable fatal autosomal recessive disorder with widespread tissue pathology. Sufferers have severe motor dysfunction as a result of defective neuronal migration and associated neurodegeneration in the neocortex and cerebellum. ZS is caused by mutations in PEX genes, which encode proteins required for the biogenesis of peroxisomes, organelles that break down toxic substances in the cells of the liver, kidneys and brain. Despite the evident importance of peroxisomes in brain development and function, the relationship between peroxisomes and neurological dysfunction is far from clear.Previous mouse knockout models of ZS have generated equivocal data regarding the link between specific peroxisomal metabolic dysfunction and disease pathogenesis. To resolve this question, this paper describes a mouse model of ZS cerebellum dysfunction generated by conditional disruption of the PEX13 gene in the brain. Mutant mice survive to weaning, but display motor abnormalities and defects in cerebellum development characterized by abnormal foliation and cell migration, and have accompanying reactive gliosis (excessive proliferation of astrocytes). The molecular basis of these changes was examined using PEX13-mutant brain in combination with cultured cerebellar neurons from embryonic day 19 (E19) PEX13-null mice. The authors demonstrate that PEX13 loss is associated with mitochondrial dysfunction, and increased levels of reactive oxygen species and cell apoptosis.PEX13-deficient mice are an important model of the neurological changes that occur in ZS. The data presented in the paper support a new theory of ZS neuropathology, in which mitochondria and reactive oxygen species play a role in disease pathogenesis. The mice should be useful models in which to test therapeutic approaches that target mitochondria and oxidative stress.