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Content archived on 2024-04-30

Zellweger Disease: Pathogenic mechanisms of organ dysfunction caused by peroxisomal deficiencies in a mouse model

Objective

Objectives:
Characterization of the pathogenic factors contributing to Zellweger disease by analysing whole animal and tissue selective peroxisome deficient transgenic mice. Delineation of neurodevelopmental abnormalities of the Zellweger transgenic mice. IdentiElcation of ultrastructural and functional abnormalities of peroxisomes in the brain and in peripheral organs of Zellweger mice.

Brief description:
The cerebro-hepato-renal syndrome of Zellweger is a fatal inherited disease caused by defects in the import of peroxisomal matrix proteins. These enzymes catalyse a variety of anabolic and catabolic reactions in lipid, amino acid, purine and peroxide metabolism. However, the relationship between defective peroxisomal function and the organ malfunctioning, in particular the disturbance of neuronal migration, has not been clarified yet. Our laboratories have recently generated a Zellweger animal model through inactivation of the PEX5 gene, encoding the import receptor for most peroxisomal matrix proteins.

The goal is to analyse thoroughly the neurodevelopmental, biochemical and peroxisomal disturbances in these mice in order to understand the basic mechanisms underlying the pathology in the brain and in the peripheral organs. Since it is at present unclear whether the central nervous system defects originate from local biochemical abnormalities due to peroxisome dysfunction in the brain or from generalized metabolic disturbances due to hepatic peroxisome deficiency, mice will also be generated with peroxisome deficiencies in selected tissues. Furthermore, within the brain the contribution of neurons and astrocytes to the diseased state will be analysed by cell specific inactivation of peroxisomes.
The results of these investigations will not only contribute to the understanding of the pathogenesis of Zellweger disease but also provide better insights in a number of diseases with similar symptoms. These include the less severe and more frequently occurring peroxisomal single enzyme defects such as e.g. X-linked adrenoleukodystrophy, but also syndromes characterized by peripheral neuropathies and epilepsy.

Keywords:
Zellweger, neuronal migration, peroxisome knock-out mouse

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Coordinator

KATHOLIEKE UNIVERSITEIT LEUVEN
EU contribution
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Address
49,Herestraat 49
3000 LOUVAIN / LEUVEN
Belgium

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