Abstract
Zellweger syndrome is a peroxisomal biogenesis disorder, characterized by the absence of peroxisomes. Peroxin (PEX) genes, which regulate the import process of peroxisome matrix proteins, are mutated in patients with Zellweger syndrome. The majority of peroxisomal reactions involve lipids, including fatty acid beta-oxidation and ether phospholipid biosynthesis. However, in the absence of peroxisomes, these metabolic pathways are severely disrupted, resulting in toxic accumulations of very long chain fatty acids and many other metabolic disturbances (Wanders and Romeijn, 1998). Previous research on mice with deletion of the PEX2 gene (PEX2-/-) revealed an absence of normal peroxisomes, central nervous system malformations with an abnormality of neuronal migration and neuronal lipid accumulation in embryonic and newborn brain (Faust, 2003; Faust and Hatten, 1997; Faust et al., 2001). Using the PEX2-/- mouse model, we characterized the distribution and time course of abnormal neuronal lipid accumulation in the postnatal mutant brain. Oil red staining in PEX2 mutant mice illustrates persistence of abnormal lipid deposits in postnatal day 3 (P3) brain but their near complete disappearance in P12-P36 PEX2 mutants, with the exceptions of olfactory bulb and ependymal lining. This loss of neuronal lipid accumulation suggests these lipids may be removed by alternate non-peroxisomal mechanisms in the developing brain. Alternatively, changing metabolic requirements in developing versus mature neurons may differentially affect lipid metabolism in the absence of peroxisomes. Lastly, our results show that myelin sheaths are visibly attenuated in the brains of PEX2 mutant mice at P15. This attenuation persists somewhat through P36. The relationship of these myelin abnormalities to specific peroxisomal lipid dysfunctions remains to be investigated.