The Experts below are selected from a list of 2034 Experts worldwide ranked by ideXlab platform
Klaus-armin Nave - One of the best experts on this subject based on the ideXlab platform.
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hdac mediated deacetylation of nf κb is critical for schwann cell Myelination
Nature Neuroscience, 2011Co-Authors: Ying Chen, Haesun A Kim, Sung Ok Yoon, John Svaren, Klaus-armin Nave, Michael O. Hottiger, Haibo Wang, Eric N. OlsonAbstract:Schwann cell Myelination is tightly regulated by timely expression of key transcriptional regulators that respond to specific environmental cues, but the molecular mechanisms underlying such a process are poorly understood. We found that the acetylation state of NF-κB, which is regulated by histone deacetylases (HDACs) 1 and 2, is critical for orchestrating the Myelination program. Mice lacking both HDACs 1 and 2 (HDAC1/2) exhibited severe Myelin Deficiency with Schwann cell development arrested at the immature stage. NF-κB p65 became heavily acetylated in HDAC1/2 mutants, inhibiting the expression of positive regulators of Myelination and inducing the expression of differentiation inhibitors. We observed that the NF-κB protein complex switched from associating with p300 to associating with HDAC1/2 as Schwann cells differentiated. NF-κB and HDAC1/2 acted in a coordinated fashion to regulate the transcriptionally linked chromatin state for Schwann cell Myelination. Thus, our results reveal an HDAC-mediated developmental switch for controlling Myelination in the peripheral nervous system.
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premature arrest of Myelin formation in transgenic mice with increased proteolipid protein gene dosage
Neuron, 1994Co-Authors: Carol Readhead, I R Griffiths, Armin Schneider, Klaus-armin NaveAbstract:Summary Proteolipid protein (PLP) is an integral membrane protein of CNS Myelin. Mutations of the X chromosome-linked PLP gene cause glial cell death and Myelin Deficiency in jimpy mice and other neurological mutants. As part of an attempt to rescue these mutants by transgenic complementation, we generated normal mouse lines expressing autosomal copies of the entire wild-type PLP gene. Surprisingly, increase of the PLP gene dosage in nonmutant mice with only 2-fold transcriptional overex-pression results in a novel phenotype characterized by severe hypoMyelination and astrocytosis, seizures, and premature death. This demonstrates that precise control of the PLP gene is a critical determinant of terminal oligodendrocyte differentiation. DysMyelination of PLP transgenic mice provides experimental evidence that Pelizaeus-Merzbacher disease, previously associated with a partial duplication of the human X chromosome, can be caused by doubling of the PLP gene dosage.
I R Griffiths - One of the best experts on this subject based on the ideXlab platform.
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processing of plp in a model of pelizaeus merzbacher disease spg2 due to the rumpshaker mutation
Glia, 2006Co-Authors: Mark Mclaughlin, Julia M Edgar, Paul Montague, J A Barrie, Saadia A Karim, D Kirkham, Christine E Thomson, I R GriffithsAbstract:The rumpshaker mutation of the X-linked Myelin proteolipid protein (PLP1) gene causes spastic paraplegia type 2 or a mild form of Pelizaeus-Merzbacher disease in man. The identical mutation occurs spontaneously in mice. Both human and murine diseases are associated with dysMyelination. Using the mouse model, we show that the low steady state levels of PLP result from accelerated proteasomal degradation rather than decreased synthesis. The T1/2 for degradation of rumpshaker PLP is 11 h compared with 23 h for wild type. A minority of newly synthesized PLP is incorporated into Myelin in the correct orientation but at a reduced rate compared with wild type. However, inhibition of proteasomal degradation does not increase the level of PLP incorporated into Myelin. As Plp null mice do not have a similar Myelin Deficiency, it is unlikely that the reduced PLP levels are the main cause of the dysMyelination. Rumpshaker oligodendrocytes also have a reduced level of other Myelin proteins, such as MBP, although the mechanisms are not yet defined but are likely to operate at a translational or post-translational level. © 2006 Wiley-Liss, Inc.
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premature arrest of Myelin formation in transgenic mice with increased proteolipid protein gene dosage
Neuron, 1994Co-Authors: Carol Readhead, I R Griffiths, Armin Schneider, Klaus-armin NaveAbstract:Summary Proteolipid protein (PLP) is an integral membrane protein of CNS Myelin. Mutations of the X chromosome-linked PLP gene cause glial cell death and Myelin Deficiency in jimpy mice and other neurological mutants. As part of an attempt to rescue these mutants by transgenic complementation, we generated normal mouse lines expressing autosomal copies of the entire wild-type PLP gene. Surprisingly, increase of the PLP gene dosage in nonmutant mice with only 2-fold transcriptional overex-pression results in a novel phenotype characterized by severe hypoMyelination and astrocytosis, seizures, and premature death. This demonstrates that precise control of the PLP gene is a critical determinant of terminal oligodendrocyte differentiation. DysMyelination of PLP transgenic mice provides experimental evidence that Pelizaeus-Merzbacher disease, previously associated with a partial duplication of the human X chromosome, can be caused by doubling of the PLP gene dosage.
Bruce J Gantz - One of the best experts on this subject based on the ideXlab platform.
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anatomical and physiological measures of auditory system in mice with peripheral Myelin Deficiency
Hearing Research, 1995Co-Authors: Renzhi Zhou, Paul J. Abbas, Jose G Assouline, Albee Messing, Bruce J GantzAbstract:Animal models with genetic abnormalities have been increasingly used in auditory research. Both TrJ mice and Po-DT-A mice are animals with peripheral Myelin Deficiency. In TrJ mice, the defect is due to a mutated PMP-22 gene. In Po-DT-A mice, the defect is produced by a transgene using the rat Po promotor to direct the expression of gene encoding for the bacterial diphtherial toxin A chain (DT-A). This study evaluates the auditory system both physiologically and histologically in these two strains of mice. Histological examination revealed that there was Myelin Deficiency of the auditory nerve fibers, accompanied by a loss of dendrites and a loss of spiral ganglion cell bodies in both strains of mice. In general, histological deficits in TrJ mice were greater than those in Po-DT-A mice. There was a strong correlation between the degree of Myelin Deficiency and the survival of spiral ganglion neurons. ABR measurements exhibited differences in threshold, latency and slope of the ABR growth function between Myelin-deficient mice and their respective controls. These results suggest that the integrity of the Myelin in the auditory nerve is important both for neural survival and for normal electrophysiological function of spiral ganglion neurons.
Cristina Ramondetti - One of the best experts on this subject based on the ideXlab platform.
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alterations of Myelin specific proteins and sphingolipids characterize the brains of acid sphingoMyelinase deficient mice an animal model of niemann pick disease type a
Journal of Neurochemistry, 2009Co-Authors: Barbara Buccinna, Marco Piccinini, Alessandro Prinetti, Federica Scandroglio, Simona Prioni, Manuela Valsecchi, Barbara Votta, Silvia Grifoni, Elisa Lupino, Cristina RamondettiAbstract:Niemann–Pick disease (NPD) type A is a neurodegenerative disorder caused by sphingoMyelin (SM) accumulation in lysosomes relying on reduced or absent acid sphingoMyelinase (ASM) activity. NPD-A patients develop progressive neurodegeneration including cerebral and cerebellar atrophy, relevant Purkinje cell and Myelin Deficiency with death within 3 years. ASM‘knock-out’ (ASMKO) mice, an animal model of NPD-A, develop a phenotype largely mimicking that of NPD-A. The mechanisms underlying Myelin formation are poorly documented in ASMKO mice. In this study we determined the content of four Myelin-specific proteins, Myelin basic protein (MBP), 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP), Myelin associated glycoprotein (MAG) and proteolipid protein (PLP), and that of Myelin-enriched sphingolipids in the brains of ASMKO and wild-type mice in early stages of post-natal (pn) life. Protein and mRNA analysis revealed that in ASMKO mice beginning from 4 post-natal weeks (wk-pn), the expression levels of MAG, CNP, and MBP were below those observed in wild-type mice and the same applied to PLP at 10 wk-pn. Moreover, at 4 wk-pn the expression of SOX10, one of the transcription factors involved in oligodendrocyte development and maintenance was lower in ASMKO mice. Lipid analysis showed that SM and the gangliosides GM3 and GM2 accumulated in the brains of ASMKO mice, as opposed to galactocerebroside and galactosulfocerebroside that, in parallel with the mRNAs of UDP-galactose ceramide galactosyltransferase and galactose-3-O-sulfotransferase 1, the two transferases involved in their synthesis, decreased. Myelin lipid analysis showed a progressive sphingoMyelin accumulation in ASMKO mice; noteworthy, of the two sphingoMyelin species known to be resolved by TLC, only that with the lower Rf accumulated. The immunohistochemical analysis showed that the reduced expression of Myelin specific proteins in ASMKO mice at 10 wk-pn was not restricted to the Purkinje layer of the cerebellar cortex but involved the cerebral cortex as well. In conclusion, reduced oligodendrocyte metabolic activity is likely to be the chief cause of Myelin Deficiency in ASMKO mice, thus shedding light on the molecular dysfunctions underlying neurodegeneration in NPD-A.
Carol Readhead - One of the best experts on this subject based on the ideXlab platform.
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premature arrest of Myelin formation in transgenic mice with increased proteolipid protein gene dosage
Neuron, 1994Co-Authors: Carol Readhead, I R Griffiths, Armin Schneider, Klaus-armin NaveAbstract:Summary Proteolipid protein (PLP) is an integral membrane protein of CNS Myelin. Mutations of the X chromosome-linked PLP gene cause glial cell death and Myelin Deficiency in jimpy mice and other neurological mutants. As part of an attempt to rescue these mutants by transgenic complementation, we generated normal mouse lines expressing autosomal copies of the entire wild-type PLP gene. Surprisingly, increase of the PLP gene dosage in nonmutant mice with only 2-fold transcriptional overex-pression results in a novel phenotype characterized by severe hypoMyelination and astrocytosis, seizures, and premature death. This demonstrates that precise control of the PLP gene is a critical determinant of terminal oligodendrocyte differentiation. DysMyelination of PLP transgenic mice provides experimental evidence that Pelizaeus-Merzbacher disease, previously associated with a partial duplication of the human X chromosome, can be caused by doubling of the PLP gene dosage.