A mouse model for Zellweger syndrome

Abstract

The cerebro-hepato-renal syndrome of Zellweger is a fatal inherited disease caused by deficient import of peroxisomal matrix proteins. The pathogenic mechanisms leading to extreme hypotonia, severe mental retardation and early death are unknown. We generated a Zellweger animal model through inactivation of the murine Pxr1 gene (formally known as Pex5) that encodes the import receptor for most peroxisomal matrix proteins. Pxr1-/- mice lacked morphologically identifiable peroxisomes and exhibited the typical biochemical abnormalities of Zellweger patients. They displayed intrauterine growth retardation, were severely hypotonic at birth and died within 72 hours. Analysis of the neocortex revealed impaired neuronal migration and maturation and extensive apoptotic death of neurons.

LIS1—no more no less

“…53,54 Zellweger syndrome patients lack PAF due to disturbed peroxi-some biogenesis 55 and have severe neuronal migration defects. 56 In a mouse model for the disease these neuronal migration defects were recapitulated, 57 suggesting a possible role for PAF-AH enzymatic activity in brain development.…”

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities†

“…The activities of urate oxidase 21 and dihydroxyacetone phosphate acyltransferase 13 were measured in liver homogenates as well as malondialdehyde levels 22 and protein carbonyl content. 23 Glucokinase activity using the continuous assay, 24 pyruvate kinase activity, 25 plasmalogens, 13 and branched chain fatty acids 26 were determined as previously described. Glycogen content was measured via amyloglycosidase digestion followed by glucose oxidase/peroxidase assay for the quantification of glucose.…”

“…Other abnormalities primarily involved the inner mitochondrial membrane as previously reported in newborn generalized Pex5 knockout mice. 13,14 Mitochondria with curled and stacked cristae ( Fig. 3D-E), tubulation of the inner membrane (Fig.…”

“…10 No abberant mitochondrial morphology was found in other Zellweger patients. 11,12 Not much attention was paid to these findings until in Pex5 knockout mice, a model for Zellweger syndrome 13 , ultrastructural changes of the inner membrane and a reduction in the activities of complex I and V of the respiratory chain were observed. 14 In the present study, a mouse model with selective elimination of peroxisomes from liver was generated to circumvent the early postnatal death of the Zellweger syndrome mouse model.…”

“…14 In the present study, a mouse model with selective elimination of peroxisomes from liver was generated to circumvent the early postnatal death of the Zellweger syndrome mouse model. 13 This allowed more extensive analysis of the subcellular changes associated with peroxisome dysfunction in hepatocytes.…”