The Neuronal Migration Defect in Mice with Zellweger Syndrome (<i>Pex5</i>Knockout) is not Caused by the Inactivity of Peroxisomal β-Oxidation

Baes, Myriam; Gressèns, Pierre; Huyghe, Steven; Nys, Katelijne De; Qi, Chao; Jia, Yaojuan; Mannaerts, Guy P.; Evrard, Philippe; Veldhoven, Paul P. Van; Declercq, Peter; Reddy, Janardan K.

doi:10.1093/jnen/61.4.368

Cited by 46 publications

(26 citation statements)

References 26 publications

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“…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.…”

Section: Methodsmentioning

confidence: 99%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

et al. 2005

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Peroxisome deficiency in men causes severe pathology in several organs, particularly in the brain and liver, but it is still unknown how metabolic abnormalities trigger these defects. In the present study, a mouse model with hepatocyte-selective elimination of peroxisomes was generated by inbreeding Pex5-loxP and albumin-Cre mice to investigate the consequences of peroxisome deletion on the functioning of hepatocytes. Besides the absence of catalase-positive peroxisomes, multiple ultrastructural alterations were noticed, including hepatocyte hypertrophy and hyperplasia, smooth endoplasmic reticulum proliferation, and accumulation of lipid droplets and lysosomes. Most prominent was the abnormal structure of the inner mitochondrial membrane, which bore some similarities with changes observed in Zellweger patients. This was accompanied by severely reduced activities of complex I, III, and V and a collapse of the mitochondrial inner membrane potential. Surprisingly, these abnormalities provoked no significant disturbances of adenosine triphosphate (ATP) levels and redox state of the liver. However, a compensatory increase of glycolysis as an alternative source of ATP and mitochondrial proliferation were observed. No evidence of oxidative damage to proteins or lipids nor elevation of oxidative stress defence mechanisms were found. Altered expression of peroxisome proliferator-activated receptor alpha (PPAR-␣) regulated genes indicated that PPAR-␣ is activated in the peroxisomedeficient cells. In conclusion, the absence of peroxisomes from mouse hepatocytes has an impact on several other subcellular compartments and metabolic pathways but is not detrimental to the function of the liver parenchyma. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). P eroxisomes are indispensable in cellular metabolism, because they harbor enzymes essential for the degradation of very long chain and branched chain fatty acids, for the conversion of cholesterol in bile acids and for the synthesis of ether phospholipids and polyunsaturated fatty acids. They also participate in the catabolism of purines, polyamines, and pipecolic acid. 1 The importance of peroxisomes is stressed by the existence of a group of genetic disorders in which one or more peroxisomal functions are impaired. The most severe is the cerebrohepatorenal syndrome of Zellweger, a peroxisome assembly disorder characterized by the absence of functional peroxisomes due to a disturbance in the peroxisomal protein import machinery. 2 At birth, Zellweger syndrome patients suffer from neurological and eye abnormalities, hypotonia, characteristic craniofacial dysmorphism, and renal cysts. 2 Hepatic pathology develops in the postnatal period, including hepatomegaly, fibrosis, micronodular cirrhosis, cholestasis, hyperbilirubinemia, and elevation of aminotransferases. 2,3 The biochemical hallmarks of this syndrome include the accumulation of very long chain and branched chain fatty aci...

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Section: Methodsmentioning

confidence: 99%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

et al. 2005

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“…Lipids were extracted from tissues, homogenized in 3.8 ml of CH 3 OH/ CHCl 3 /H 2 O (2:1:0.8), using a Polytron tissue homogenizer, 24 and separated into neutral lipids, fatty acids, and phospholipids by solid phase extraction (Bond Elut NH 2 column, 500 mg; Varian Benelux, Sint-Katelijne-Waver, Belgium). 20,25 Cholesterol, 26 cholesteryl esters, 26 neutral glycerolipids, 27 and phosphorus content of the phospholipid fraction 28 were determined as previously described. The content of DHA in the phospholipid fraction was determined by GC analysis as previously described.…”

Section: Lipid Analysismentioning

confidence: 99%

“…29 Phytanic, pristanic acid, and C 26:0 were quantified by GC-MS analysis in phospholipids and neutral lipids. 20 …”

Section: Lipid Analysismentioning

confidence: 99%

“…It is characterized by neonatal hypotonia and seizures, neuronal migration defects, and early postnatal death. 13 In contrast, in the mouse the neurodevelopmental abnormalities, hypotonia, and seizures are absent, 20 but a significant fraction of the mice dies postnatally with a general failure to thrive related to metabolic problems. 32 The surviving knockouts develop during early adulthood abnormal extension reflexes of the limbs, biochemically and histopathologically paralleled by an overexpression of catalase in glial cells, astrogliosis and microglia activation, and possible signs of glial cell degeneration in the CNS gray matter, ie, features not known from human patients.…”

Section: Murine Mfp-2 Deficiency Shows Major Differences To Human Inamentioning

confidence: 99%

“…We recently generated mouse models with peroxisome assembly defects (Pex5 knockout) 18 or with peroxisomal ␤-oxidation defects (MFP-2 19 and MFP-1/MFP-2 knockout 20 ) to investigate the pathogenesis of peroxisomal disorders and to further explore the role of peroxisomes in brain. In contrast to the situation in humans, a Zellweger-like pathomorphology was only seen in the model with peroxisome assembly defects (Pex5 knockout) 18 but not in mice with peroxisomal ␤-oxidation defects.…”

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Peroxisomal Multifunctional Protein-2 Deficiency Causes Motor Deficits and Glial Lesions in the Adult Central Nervous System

Huyghe

Schmalbruch

Hulshagen

et al. 2006

The American Journal of Pathology

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In humans, mutations inactivating multifunctional protein-2 (MFP-2), and thus peroxisomal ␤-oxidation, cause neuronal heterotopia and demyelination, which is clinically reflected by hypotonia, seizures, and death within the first year of life. In contrast, our recently generated MFP-2-deficient mice did not show neurodevelopmental abnormalities but exhibited aberrations in bile acid metabolism and one of three of them died early postnatally. In the postweaning period, all survivors developed progressive motor deficits, including abnormal cramping reflexes of the limbs and loss of mobility, with death at 6 months. During the last decades it has been clearly established that peroxisomes are ubiquitously present in mammalian tissues. These organelles are involved in multiple processes such as the catabolism and synthesis of lipids and sterols and the degradation of hydrogen peroxide. Peroxisomal ␤-oxidation, in which multifunctional protein-2 (MFP-2) plays a pivotal role, is crucial for the breakdown of very-long-chain fatty acids, branched chain fatty acids, and cholesterol.

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Peroxisomal Disorders

Faust

2018

Developmental Neuropathology

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The Neuronal Migration Defect in Mice with Zellweger Syndrome (Pex5Knockout) is not Caused by the Inactivity of Peroxisomal β-Oxidation

Cited by 46 publications

References 26 publications

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

Peroxisomal Multifunctional Protein-2 Deficiency Causes Motor Deficits and Glial Lesions in the Adult Central Nervous System

Peroxisomal Disorders

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