Peroxisome biogenesis disorders: the role of peroxisomes and metabolic dysfunction in developing brain

Peroxisome biogenesis disorders, of which Zellweger syndrome is the most severe, result in severe neurological dysfunction associated with abnormal CNS neuronal migrations due to the lack of functional peroxisomes. The PEX2-/- mouse model for Zellweger syndrome has enabled us to evaluate the role of peroxisomes in the development and functioning of the nervous system. These studies have shown that, in addition to disturbances in neuronal migration in developing cerebral cortex and cerebellum, defects in neuronal differentiation, proliferation and survival may also contribute to the CNS malformations. However, owing to the multiorgan dysfunction in peroxisomal disorders, it has been difficult to clearly define an intrinsic role for the peroxisome in brain cells. The use of several in vitro Cell Culture assays to evaluate the migration and differentiation of cerebellar neurons demonstrates a persistence of defects in peroxisome-deficient neurons. The absence of potential systemically derived, extrinsic factors in these in vitro systems indicates that CNS intrinsic defects contribute to the pathogenesis of disease in these disorders. However, bile acid treatment also increases the survival and growth of PEX2-/- mice and improves some aspects of cerebellar development, indicating that extrinsic factors also affect the developing peroxisome-deficient brain. Therefore, the final phenotype of nervous system dysfunction in peroxisomal disorders will reflect a combination of both CNS intrinsic and extrinsic factors.