title: Characterisation of a Zellweger Syndrome Mouse Mode
Creators: name: Müller, Christina Catharina
Publisher: name: Griffith University
Year: 2009
Subjects: subject: Zellweger syndrome (ZS)
subject: Peroxisomal disorders

description: Abstract: Zellweger syndrome (ZS) represents the most severe form of the spectrum of autosomal recessive peroxisomal disorders. These disorders result from mutations in PEX genes, which encode proteins (peroxins) that are required for peroxisome biogenesis. The inability to form functional peroxisomes in ZS leads to the loss of peroxisomal functions such as very long chain fatty acid oxidation and synthesis of bile acids and plasmalogens. Clinically, this results in a complex array of symptoms of which the neuropathogenesis is most pronounced. The mechanism behind the neuropathogenesis (and other clinical symptoms) is not yet understood. Over the last two decades, several murine models that feature most ZS symptoms have been generated to aid in understanding the pathogenesis of this debilitating disease. However, the utility of some of these mouse mutants has been limited by the neonatal lethality of pups. Recent work in this laboratory resulted in the generation of a brain specific Pex13 mutant – Pex13 encodes a peroxisomal membrane protein essential for peroxisome biogenesis. This Pex13 brain mutant was generated by nestin-driven, Cre recombinase-mediated, tissue specific disruption of Pex13. Pex13 brain mutants feature many biochemical characteristics of a milder form of ZS and exhibits postnatal survival, making them suitable for studying postnatal neuropathogenesis in ZS. The goal of this thesis was to characterise macroscopic and neurological changes of the Pex13 brain mutant, and ultimately to gain a better understanding of the neuropathogenesis of ZS. An average excision level of Pex13 of 70-90% was found to result in a pronounced mutant phenotype in all Pex13 brain mutants. This macroscopic phenotype was characterised by severe growth retardation, early death, and prominent abnormalities in motor control. A higher level of Pex13 excision did not result in earlier death or a more pronounced phenotype. However, a correlation was identified between disease severity and pup size at weaning, suggestive of intra-litter competition being a factor impacting on survival. Consistent with the observed motor control abnormalities, Pex 13 brain mutants exhibited a pronounced phenotype in the cerebellum, the primary brain region involved in motor control. Cerebellar defects included abnormalities in the formation of folia and their separating fissures, a delayed migration of granule cells, and abnormal development of Purkinje cells. In addition, there were indications of a smaller cerebellum size, and a decreased granule precursor cell population. Cholesterol and redox homeostasis were investigated as possible mechanisms underlying cerebellar disease pathology. Cholesterol levels were found to be normal in all brain regions, and no significant indications of oxidative stress were observed., suggesting that these were factors not contributing to cerebellum neuropathogenesis. Instead, malnourishment was suggested as a potential contributing factor to disease pathogenesis, consistent with other studies showing that nutrient deficiency has irreversible effects on brain development. A significant finding of this study was the identification of a striking level of reactive gliosis, indicative for neuronal damage, in the cerebellum and other regions of the brain. A hypothesis that arises from these findings is that reactive gliosis is induced by apoptotic cells, and may relate to recent observation of α-synuclein accumulation in brain of Pex13 brain mutants. Furthermore, it is conceivable that in contrast to its neuroprotecitve role, reactive gliosis may initiate a self-perpetuating cycle of release of neurotoxic substances, resultant in neuronal death, and further activation of reactive gliosis. Finally, a model is proposed as a possible explanation of how a local peroxisome deficiency within neuronal cell dendrites could contribute to the cerebellar phenotype of Pex13 brain mutants.