The mechanism of arrest of neuronal migration in the Zellweger malformation: An hypothesis based upon cytoarchitectonic analysis

Evrard, Philippe; Caviness, Verne S.; Prats-Vinas, J.; Lyon, G

doi:10.1007/bf00689761

Cited by 164 publications

(64 citation statements)

References 25 publications

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“…Other peaks correspond to the following: 3a,6a,7a,12a-tetrahydroxy-5#-cholestanoic acid (tentatively identified, see text), 12 ml, cholic acid, 15 ml, 24-OH-THCA, 19 ml, 25R and 25S-THCA, 35 and 37 ml, respectively. C29-dicarboxylic acid was identified in the fraction that eluted at 20 ml.…”

Section: Resultsmentioning

confidence: 97%

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Defective peroxisomal cleavage of the C27-steroid side chain in the cerebro-hepato-renal syndrome of Zellweger.

Kase¹,

Björkhem²,

Hågå³

et al. 1985

J. Clin. Invest.

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Based on in vitro work with rat liver, we recently suggested that the peroxisomal fraction is most important for the oxidation of 3a,7a,12a-trihydroxy-5,8-cholestanoic acid (THCA) into cholic acid. The cerebro-hepato-renal syndrome of Zellweger is a fatal recessive autosomal disorder, the most characteristic histological feature of which is a virtual absence of peroxisomes in liver and kidneys. This disease offers a unique opportunity to evaluate the relative importance of peroxisomes in bile acid biosynthesis. A child with Zellweger syndrome was studied in the present work. In accordance with previous work, there was a considerable accumulation of THCA, 3a,7a,12a,24-tetrahydroxy-5,6-cholestanoic acid (24-OH-THCA), 3a,7a,12a-trihydroxy-27-carboxymethyl-5#6-cholestan-26-oic acid (C2-dicarboxylic acid), and 3a,7a-dihydroxy-5#-cholestanoic acid in serum. In addition, a tetrahydroxylated 51e-cholestanoic acid with all the hydroxyl groups in the steroid nucleus was found.3H-Labeled 5W-cholestane-3a,7a,12a-triol was administered intravenously together with 14C-labeled cholic acid. There was a rapid incorporation of 3H in THCA and a slow incorporation into cholic acid. The specific radioactivity of 3H in THCA was about one magnitude higher than that in cholic acid. The conversion was evaluated by following the increasing ratio between 3H and 14C in biliary cholic acid. The rate of incorporation of 3H in cholic acid was considerably less than previously reported in experiments with healthy subjects, and the maximal conversion of the triol into cholic acid was only 15-20%. About the same rate of conversion was found after oral administration of 3H-THCA. Both in the experiment with 3H-5W6cholestane-3a,7a,12a-triol and with 3H-THCA, there was an efficient incorporation of 3H in the above unidentified tetrahydroxylated 5#-cholestanoic acid. There was only slow incorporation of radioactivity into 24-OH-THCA and into the C2-dicarboxylic acid. From the specific activity decay curve of "'C in cholic acid obtained after intravenous injection of 14C-cholic acid, the pool size of cholic acid was calculated to be 24 mg/M2 and the daily production rate to 9 mg/M2 per d.This corresponds to a reduction of -85 and 90%, respectively, when compared with normal infants. It is concluded that liver peroxisomes are essential in the normal conversion of THCA to cholic acid. In the Zellweger syndrome this conversion is Address correspondence to Dr. Pedersen, Institute for Nutrition Research.Received for publication 9 January 1984 and in revised form 12 October 1984. defective, and as a consequence the accumulated THCA is either excreted as such or transformed into other metabolites by hydroxylation or side chain elongation. The accumulation of THCA, as well as the similar rate of conversion of 5#-cholestane-3a,7a,12a-triol and THCA into cholic acid, support the contention that the 26-hydroxylase pathway with intermediate formation of THCA is the most important pathway for formation of cholic acid in man.

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Section: Resultsmentioning

confidence: 97%

“…Normal peroxisomal structures could not be recognized. In the central nervous system neuronal migration arrest typical for Zellweger syndrome (12) was observed.…”

Section: Methodsmentioning

confidence: 99%

Defective peroxisomal cleavage of the C27-steroid side chain in the cerebro-hepato-renal syndrome of Zellweger.

Kase¹,

Björkhem²,

Hågå³

et al. 1985

J. Clin. Invest.

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“…Some form of cortical malformation is observed in at least 14% of all cases of epilepsy (Meencke and Veith, 1992) and in ϳ40% of severe or intractable cases (Hardiman et al, 1988;Farrell et al, 1992). Although the etiologies of cortical malformations are poorly understood, they have been postulated to arise from disturbances in cell proliferation, neuronal migration, and/or programmed cell death (Evrard et al, 1978;Rakic, 1988;Barkovich et al, 1992;Meencke and Veith, 1992;Mouritzen-Dam, 1992;Palmini et al, 1993;Rorke, 1994).…”

Section: Abstract: Cortical Heterotopia; Epilepsy; Neuronal Migratiomentioning

confidence: 99%

A Genetic Animal Model of Human Neocortical Heterotopia Associated with Seizures

et al. 1997

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Malformations of the human neocortex are commonly associated with developmental delays, mental retardation, and epilepsy. This study describes a novel neurologically mutant rat exhibiting a forebrain anomaly resembling the human neuronal migration disorder of double cortex. This mutant displays a telencephalic internal structural heterotopia (tish) that is inherited in an autosomal recessive manner. The bilateral heterotopia is prominent below the frontal and parietal neocortices but is rarely observed in temporal neocortex. Neurons in the heterotopia exhibit neocortical-like morphologies and send typical projections to subcortical sites; however, characteristic lamination and radial orientation are disturbed in the heterotopia. The period of neurogenesis during which cells in the heterotopia are generated is the same as in the normotopic neocortex; however, the cells in the heterotopia exhibit a "rim-to-core" neurogenetic pattern rather than the characteristic "inside-out" pattern observed in normotopic neocortex. Similar to the human syndrome of double cortex, some of the animals with the tish phenotype exhibit spontaneous recurrent electrographic and behavioral seizures.The tish rat is a unique neurological mutant that shares several features with a human cortical malformation associated with epilepsy. On the basis of its regional connectivity, histological composition, and period of neurogenesis, the heterotopic region in the tish rat is neocortical in nature. This neurological mutant represents a novel model system for investigating mechanisms of aberrant neocortical development and is likely to provide insights into the cellular and molecular events contributing to seizure development in dysplastic neocortex.

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“…First, the most severe peroxisome biogenesis disorder, Zellweger syndrome, and some single peroxisomal ␤-oxidation enzyme deficiencies cause cytoarchitectonic abnormalities including cortical neuronal migration defects, malformations of the cerebellum and of the inferior medullary olives (Evrard et al, 1978;Gould et al, 2001). These defects were recapitulated in Zellweger mouse models (Baes and Van Veldhoven, 2006).…”

Section: Introductionmentioning

confidence: 99%

Absence of Functional Peroxisomes from Mouse CNS Causes Dysmyelination and Axon Degeneration

Hulshagen¹,

Krysko²,

Bottelbergs³

et al. 2008

J. Neurosci.

100

110

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Peroxisomal metabolism is essential for normal brain development both in men and in mice. Using conditional knock-out mice, we recently showed that peroxisome deficiency in liver has a severe and persistent impact on the formation of cortex and cerebellum, whereas absence of functional peroxisomes from the CNS only causes developmental delays without obvious alteration of brain architecture.We now report that a substantial fraction of the latter Nes-Pex5 knock-out mice survive into adulthood but develop progressive motoric and coordination problems, impaired exploration, and a deficit in cognition and die before the age of 6 months. Histopathologically, both the white and gray matter of the CNS displayed a region-specific accumulation of neutral lipids, astrogliosis and microgliosis, upregulation of catalase, and scattered cell death. Nes-Pex5 knock-out mice featured a dramatic reduction of myelin staining in corpus callosum, whereas cerebellum and other white matter tracts were less affected or unchanged. This was accompanied by a depletion of alkenylphospholipids in myelin and differentially reduced immunoreactivity of myelin proteins. EM analysis revealed that myelin wrappings around axons did still form, but they showed a reduction in thickness relative to axon diameters. Remarkably, multifocal axonal damage occurred in the corpus callosum. Thereby, debris accumulated between axolemma and inner myelin surface and axons collapsed, although myelin sheaths remained present. These anomalies of myelinated axons were already present in juvenile mice but aggravated in adulthood. Together, loss of CNS peroxisomal metabolism both affects myelin sheaths and axonal integrity possibly via independent pathways.

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The mechanism of arrest of neuronal migration in the Zellweger malformation: An hypothesis based upon cytoarchitectonic analysis

Cited by 164 publications

References 25 publications

Defective peroxisomal cleavage of the C27-steroid side chain in the cerebro-hepato-renal syndrome of Zellweger.

Defective peroxisomal cleavage of the C27-steroid side chain in the cerebro-hepato-renal syndrome of Zellweger.

A Genetic Animal Model of Human Neocortical Heterotopia Associated with Seizures

Absence of Functional Peroxisomes from Mouse CNS Causes Dysmyelination and Axon Degeneration

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