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

Huyghe, Steven; Schmalbruch, Henning; Hulshagen, Leen; Veldhoven, Paul P. Van; Baes, Myriam; Hartmann, Dieter

doi:10.2353/ajpath.2006.041220

Cited by 43 publications

(67 citation statements)

References 45 publications

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“…Complicating this matter is the observation that the knock-out mouse model deviates from the patients, because no developmental myelin defects were seen in MFP-2 knock-out mice (Huyghe et al, 2006b). Although VLCFA were often claimed to contribute to membrane abnormalities, there is no definitive proof of their pathogenic role.…”

Section: Myelin Anomaliesmentioning

confidence: 97%

“…We found no evidence for neuromuscular abnormalities in either mouse model. In the brain, Nes-Pex5 and MFP-2 knock-out mice share lipid accumulations, astrogliosis and microgliosis in the gray matter, and increased expression of catalase (Huyghe et al, 2006b).…”

Section: Pathogenesis Of Motoric and Cognitive Impairmentmentioning

confidence: 99%

“…progressive motoric inability, lethargy, and death before the age of 6 months (Huyghe et al, 2006b). We found no evidence for neuromuscular abnormalities in either mouse model.…”

Section: Pathogenesis Of Motoric and Cognitive Impairmentmentioning

confidence: 99%

“…Five-micrometer-thick sections were processed as previously described (Huyghe et al, 2006b) except that, depending on the antibody, trypsinization or heating of tissues in citrate buffer was applied for antigen retrieval. The following primary antibodies were used: monoclonal mouse antibodies against GFAP (SigmaAldrich), PLP (Millipore Bioscience Research Reagents), nonphosphorylated neurofilament SMI32 (Sternberger, Baltimore, MD), amyloid precursor protein (APP) (Millipore Bioscience Research Reagents), cleaved caspase-3 (Cell Signaling Technology, Danvers, MA), CC1 (Calbiochem, San Diego, CA), CD45 (BD Pharmingen, San Diego, CA), 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase (CNP) (Sternberger); monoclonal rat antibody against F4/80 (Serotec, Oxford, UK), and polyclonal rabbit antibodies against CD3 (BD Pharmingen), MBP, and catalase already described for Western blot analysis.…”

Section: Histological Analysismentioning

confidence: 99%

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

Hulshagen¹,

Krysko²,

Bottelbergs³

et al. 2008

J. Neurosci.

100

113

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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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Section: Myelin Anomaliesmentioning

confidence: 97%

Section: Pathogenesis Of Motoric and Cognitive Impairmentmentioning

confidence: 99%

“…progressive motoric inability, lethargy, and death before the age of 6 months (Huyghe et al, 2006b). We found no evidence for neuromuscular abnormalities in either mouse model.…”

Section: Pathogenesis Of Motoric and Cognitive Impairmentmentioning

confidence: 99%

Section: Histological Analysismentioning

confidence: 99%

See 2 more Smart Citations

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

Hulshagen¹,

Krysko²,

Bottelbergs³

et al. 2008

J. Neurosci.

100

113

View full text Add to dashboard Cite

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“…[12][13][14][15][16] These results indicate that peroxisomal fatty acid β-oxidation in glial cells is indispensable for the maintenance of myelin. In the central nervous system (CNS), ABCD1 is highly expressed in astrocytes and microglia in the subcortical and cerebellar white matter.…”

mentioning

confidence: 71%

Very Long Chain Fatty Acid β-Oxidation in Astrocytes: Contribution of the ABCD1-Dependent and -Independent Pathways

Morita

Shinbo

Asahi

et al. 2012

Biological & Pharmaceutical Bulletin

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Very long chain fatty acid (VLCFA) metabolism in astrocytes is important for the maintenance of myelin structure in central nervous system. To analyze the contribution of the ABCD1-dependent and -independent pathways to VLCFA metabolism in astrocytes, we prepared human glioblastoma U87 cells with a silencing of ABCD1 and primary astrocytes from abcd1-deficient mice, and measured fatty acid β-oxidation in the presence or absence of a potent inhibitor of carnitine palmitoyltransferase I, 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). In U87 cells, C24:0 β-oxidation was decreased to ca. 70% of the control in the presence of POCA, and the activity was further decreased to ca. 20% by the silencing of ABCD1. In mouse primary astrocytes, C24:0 β-oxidation was also decreased to ca. 70% of the control in the presence of POCA. The C24:0 β-oxidation in Abcd1-deficient primary astrocytes was ca. 60% of the wild-type cells and the activity was further decreased to ca. 25% in the presence of POCA. Compared to human skin fibroblasts, in which VLCFA β-oxidation is not significantly inhibited by POCA, approximately one-third of the overall VLCFA β-oxidation was inhibited in both types of astrocytic cells. These results suggest that VLCFA is indeed β-oxidized in ABCD1-dependent pathway, but the ABCD1-independent peroxisomal and mitochondrial β-oxidation pathways significantly contribute to VLCFA β-oxidation in astrocytic cells.Key words very long chain fatty acid β-oxidation; astrocyte; ABCD1; peroxisome; mitochondria Peroxisomes are single membrane organelles that are present in almost all eukaryotic cells. The peroxisomes are involved in a variety of metabolic processes, including the β-oxidation of fatty acids, especially very long chain fatty acids (VLCFA, >C22), and the synthesis of ether phospholipids and bile acids in mammals.1) Transport of substrates for fatty acid β-oxidation across the peroxisomal membrane is an essential step in this metabolism. Peroxisomal ATP-binding cassette (ABC) proteins have been implicated in this transport.To date, three ABC proteins, classified into "subfamily D," have been identified in mammalian peroxisomes. These are adrenoleukodystrophy protein (ALDP/ABCD1),2) ALDP-related protein (ALDRP/ABCD2) 3) and a 70-kDa peroxisomal membrane protein (PMP70/ABCD3). 4) Dysfunction of ABCD1 causes the human genetic disorder X-linked adrenoleukodystrophy (X-ALD) characterized by an accumulation of VLCFA because of the impaired peroxisomal β-oxidation of VLCFA.5) VLCFA β-oxidation in X-ALD patient fibroblasts was restored by the expression of ABCD1. Likewise, the expression of ABCD2, which has a high sequence similarity to ABCD1, also restored VLCFA β-oxidation in X-ALD fibro blasts.6) In analogy to the role of Pxa1p/Pxa2p, 7) yeast peroxisomal half-ABC transporters, which is involved in the transport of acyl-CoA, ABCD1 and ABCD2 are thought to be involved in the metabolic transport of VLCFA-CoA. 8,9) ABCD3 is suggested to be involved in the metabolic transport of long chain fatty acids (LCFA)...

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Metabolic etiologies in West syndrome

2018

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SummaryWest syndrome (WS) is an early life epileptic encephalopathy associated with infantile spasms, interictal electroencephalography (EEG) abnormalities including high amplitude, disorganized background with multifocal epileptic spikes (hypsarrhythmia), and often neurodevelopmental impairments. Approximately 64% of the patients have structural, metabolic, genetic, or infectious etiologies and, in the rest, the etiology is unknown. Here we review the contribution of etiologies due to various metabolic disorders in the pathology of WS. These may include metabolic errors in organic molecules involved in amino acid and glucose metabolism, fatty acid oxidation, metal metabolism, pyridoxine deficiency or dependency, or acidurias in organelles such as mitochondria and lysosomes. We discuss the biochemical, clinical, and EEG features of these disorders as well as the evidence of how they may be implicated in the pathogenesis and treatment of WS. The early recognition of these etiologies in some cases may permit early interventions that may improve the course of the disease.

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

Cited by 43 publications

References 45 publications

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

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

Very Long Chain Fatty Acid β-Oxidation in Astrocytes: Contribution of the ABCD1-Dependent and -Independent Pathways

Metabolic etiologies in West syndrome

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