The Experts below are selected from a list of 633 Experts worldwide ranked by ideXlab platform
James Garbern - One of the best experts on this subject based on the ideXlab platform.
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Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes.
Human Mutation, 2020Co-Authors: Grace M Hobson, James Garbern, Edwin H. Kolodny, Erik A Sistermans, Zhong Huang, Karen Sperle, Peter K. Rogan, Sakkubai Naidu, Franca CambiAbstract:Mutations in the Proteolipid Protein 1 (PLP1) gene cause the X-linked dysmyelinating diseases Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia 2 (SPG2). We examined the severity of the following mutations that were suspected of affecting levels of PLP1 and DM20 RNA, the alternatively spliced products of PLP1: c.453G>A, c.453G>T, c.453G>C, c.453+2T>C, c.453+4A>G, c.347C>A, and c.453+28_+46del (the old nomenclature did not include the methionine codon: G450A, G450T, G450C, IVS3+2T>C, IVS3+4A>G, C344A, and IVS3+28-+46del). These mutations were evaluated by information theory-based analysis and compared with mRNA expression of the alternatively spliced products. The results are discussed relative to the clinical severity of disease. We conclude that the observed PLP1 and DM20 splicing patterns correlated well with predictions of information theory-based analysis, and that the relative strength of the PLP1 and DM20 donor splice sites plays an important role in PLP1 alternative splicing. Hum Mutat 27(1), 69–77, 2006. © 2005 Wiley-Liss, Inc.
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diffusion tensor imaging of patients with Proteolipid Protein 1 gene mutations
Journal of Neuroscience Research, 2014Co-Authors: Jeremy J Laukka, Malek I Makki, Tori Lafleur, Jeffrey A Stanley, John Kamholz, James GarbernAbstract:Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder of the central nervous system (CNS) caused by a wide variety of mutations affecting Proteolipid Protein 1 (PLP1). We assessed the effects of PLP1 mutations on water diffusion in CNS white matter by using diffusion tensor imaging. Twelve patients with different PLP1 point mutations encompassing a range of clinical phenotypes were analyzed, and the results were compared with a group of 12 age-matched controls. The parallel (λ// ), perpendicular (λ⊥ ), and apparent diffusion coefficients (ADC) and fractional anisotropy were measured in both limbs of the internal capsule, the genu and splenium of corpus callosum, the base of the pons, and the cerebral peduncles. The mean ADC and λ⊥ in the PMD patient group were both significantly increased in all selected structures, except for the base of the pons, compared with controls. PMD patients with the most severe disease, however, had a significant increase of both λ// and λ⊥ . In contrast, more mildly affected patients had much smaller changes in λ// and λ⊥ . These data suggest that myelin, the structure responsible in part for the λ⊥ barrier, is the major site of disease pathogenesis in this heterogeneous group of patients. Axons, in contrast, the structures mainly responsible for λ// , are much less affected, except within the subgroup of patients with the most severe disease. Clinical disability in patients with PLP1 point mutation is thus likely determined by the extent of pathological involvement of both myelin and axons, with alterations of both structures causing the most severe disease. © 2014 Wiley Periodicals, Inc.
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Variable Expression of a Novel PLP1 Mutation in Members of a Family With Pelizaeus-Merzbacher Disease
Journal of Child Neurology, 2009Co-Authors: Aviva Fattal-valevski, Grace M Hobson, James Garbern, Miriam S. Dimaio, Fuki M. Hisama, Angelique Davis-williams, Maurice J. Mahoney, Edwin H. Kolodny, Gregory M. PastoresAbstract:Pelizaeus-Merzbacher disease is a rare X-linked disorder caused by mutations of the Proteolipid Protein 1 gene that encodes a structural component of myelin. It is characterized by progressive psychomotor delay, nystagmus, spastic quadriplegia, and cerebellar ataxia. Variable clinical expression was seen in 5 members of a family bearing a novel missense mutation in Proteolipid Protein 1, c.619T>C. Symptomatic patients included a 6-year-old girl, her younger brother, and their maternal uncle, a 29-year-old college graduate initially diagnosed with cerebral palsy; their brain magnetic resonance imaging studies showed diffuse dysmyelination. The mother had a history of delayed walking, achieved independently by age 3; she and the maternal grandmother were asymptomatic on presentation. Review of clinical information and family history led to consideration of Pelizaeus-Merzbacher disease. Subsequent identification of the causal mutation enabled preimplantation genetic diagnosis and the birth of an unaffected c...
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steroid responsive neurologic relapses in a child with a Proteolipid Protein 1 mutation
Neurology, 2007Co-Authors: Mark P Gorman, M R Golomb, L E Walsh, Grace M Hobson, James Garbern, Revere P Kinkel, Basil T Darras, David K Urion, Yaman Z EksiogluAbstract:A 10-year-old boy developed corticosteroid-responsive relapsing neurologic signs, including nystagmus and ataxia. MRI revealed multifocal T2 white matter hyperintensities; several were gadolinium-enhancing. CSF contained oligoclonal bands. Although the patient met criteria for multiple sclerosis (MS), the Proteolipid Protein-1 gene (PLP1) contained a mutation in exon 3B (c.409C>T), predicting a tryptophan-for-arginine substitution. This case raises questions about the role of inflammation in PLP1-related disorders and, conversely, PLP1 mutations in MS.
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Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease
Genetics in Medicine, 2006Co-Authors: Stephanie Hurst, James Garbern, Angela TrepanierAbstract:Purpose: Pelizaeus-Merzbacher disease and spastic paraplegia type 2 are allelic X -linked disorders that principally affect males and are caused by mutations in the Proteolipid Protein 1 gene. Neurologic symptoms are occasionally observed in carrier females, and anecdotal evidence suggests that these clinical signs are more likely in families with affected males. We analyze 40 pedigrees to determine whether such a link exists. Methods: From a chart review of patients from Wayne State University, we categorize patients according to disease severity and type of genetic lesion within the Proteolipid Protein 1 gene. We then analyze the clinical data using nonparametric t tests and analyses of variance. Results: Our analyses formally demonstrate the link between mild disease in males and symptoms in carrier female relatives. Conversely, mutations causing severe disease in males rarely cause clinical signs in carrier females. The greatest risk of disease in females is found for nonsense/indel or null mutations. Missense mutations carry moderate risk. The lowest risk, which represents the bulk of families with Pelizaeus-Merzbacher disease, is associated with Proteolipid Protein 1 gene duplications. Conclusions: Effective genetic counseling of Pelizaeus-Merzbacher disease and spastic paraplegia carrier females must include an assessment of disease severity in affected male relatives.
Ken Inoue - One of the best experts on this subject based on the ideXlab platform.
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Prenatal interphase FISH diagnosis of PLP1 duplication associated with Pelizaeus–Merzbacher disease
Prenatal Diagnosis, 2020Co-Authors: Ken Inoue, James R. Lupski, Makoto Kanai, Yuzo Tanabe, Takeo Kubota, Catherine D. Kashork, Keiko Wakui, Yoshimitsu Fukushima, Lisa G. ShafferAbstract:A submicroscopic genomic duplication in Xq22.2 that contains the entire Proteolipid Protein 1 gene (PLP1) is responsible for the majority of Pelizaeus–Merzbacher disease (PMD) patients. We previously developed an interphase FISH assay to screen for PLP1 duplications in PMD patients using peripheral blood and lymphoblastoid cell lines. This assay has been utilized as a clinical diagnostic test in our cytogenetics laboratory. To expand usage of the interphase FISH assay to prenatal diagnosis of PLP1 duplications, we examined three PMD families with PLP1 duplications utilizing aminiotic fluid samples. In two families the FISH assay revealed fetuses with PLP1 duplications, whereas the other fetus showed a normal copy number of PLP1. Haplotype analyses, as well as an additional FISH analysis using postnatal blood samples, confirmed the results of the prenatal analyses. Our study demonstrates utility of the interphase FISH assay in the prenatal diagnosis of PLP1 duplications in PMD. Copyright © 2001 John Wiley & Sons, Ltd.
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Pelizaeus–Merzbacher Disease and Spastic Paraplegia Type 2
Genomic Disorders, 2020Co-Authors: Ken InoueAbstract:Pelizaeus-Merzbacher disease (PMD) is a genomic disorder that is caused by altered dosage of a single gene, Proteolipid Protein 1 (itPLP1). Either duplication or deletion of itPLP1-containing genomic regions on chromosome Xq22.2 results in a severe leukodystrophy characterized by deficits of myelination in the central nervous system (itCNS). In this chapter, the molecular and genomic mechanisms for rearrangements causing PMD are reviewed, emphasizing differences in comparison to Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP)
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Pelizaeus-Merzbacher Disease: Molecular and Cellular Pathologies and Associated Phenotypes.
Advances in Experimental Medicine and Biology, 2019Co-Authors: Ken InoueAbstract:Pelizaeus-Merzbacher disease (PMD) represents a group of disorders known as hypomyelinating leukodystrophies, which are characterized by abnormal development and maintenance of myelin in the central nervous system. PMD is caused by different types of mutations in the Proteolipid Protein 1 (PLP1) gene, which encodes a major myelin membrane lipoProtein. These mutations in the PLP1 gene result in distinct cellular and molecular pathologies and a spectrum of clinical phenotypes. In this chapter, I discuss the historical aspects and current understanding of the mechanisms underlying how different PLP1 mutations disrupt the normal process of myelination and result in PMD and other disorders.
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Gene suppressing therapy for Pelizaeus-Merzbacher disease using artificial microRNA
JCI insight, 2019Co-Authors: Heng Li, Hironori Okada, Sadafumi Suzuki, Kazuhisa Sakai, Hitomi Izumi, Yukiko Matsushima, Noritaka Ichinohe, Yu-ichi Goto, Takashi Okada, Ken InoueAbstract:Copy number increase or decrease of certain dosage-sensitive genes may cause genetic diseases with distinct phenotypes, conceptually termed genomic disorders. The most common cause of Pelizaeus-Merzbacher disease (PMD), an X-linked hypomyelinating leukodystrophy, is genomic duplication encompassing the entire Proteolipid Protein 1 (PLP1) gene. Although the exact molecular and cellular mechanisms underlying PLP1 duplication, which causes severe hypomyelination in the central nervous system, remain largely elusive, PLP1 overexpression is likely the fundamental cause of this devastating disease. Here, we investigated if adeno-associated virus–mediated (AAV-mediated) gene-specific suppression may serve as a potential cure for PMD by correcting quantitative aberrations in gene products. We developed an oligodendrocyte-specific Plp1 gene suppression therapy using artificial microRNA under the control of human CNP promoter in a self-complementary AAV (scAAV) platform. A single direct brain injection achieved widespread oligodendrocyte-specific Plp1 suppression in the white matter of WT mice. AAV treatment in Plp1-transgenic mice, a PLP1 duplication model, ameliorated cytoplasmic accumulation of Plp1, preserved mature oligodendrocytes from degradation, restored myelin structure and gene expression, and improved survival and neurological phenotypes. Together, our results provide evidence that AAV-mediated gene suppression therapy can serve as a potential cure for PMD resulting from PLP1 duplication and possibly for other genomic disorders.
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Drug screening for Pelizaeus-Merzbacher disease by quantifying the total levels and membrane localization of PLP1
Molecular genetics and metabolism reports, 2019Co-Authors: Takeshi Kouga, Ken Inoue, Shiro Koizume, Shiho Aoki, Eriko F. Jimbo, Takanori Yamagata, Hitoshi OsakaAbstract:Abstract Background Pelizaeus-Merzbacher disease (PMD) is caused by point mutations or copy number changes in the Proteolipid Protein 1 gene (PLP1). PLP1 is exclusively localized in the myelin sheath of oligodendrocytes. Amino acid-substituted PLP1 Protein is unable to fold properly and is subsequently degraded and/or restrictedly translated, resulting in a decrease in the PLP1 Protein level and a failure to localize to the membrane. Furthermore, misfolded Proteins increase the burden on the intracellular quality control system and trafficking, finally resulting in cell apoptosis. The objective of this study was to identify therapeutic chemicals for PMD by quantifying the total levels and membrane localization of PLP1. Method We established a cell line stably expressing PLP1A243V fused with green fluorescent Protein in oligodendrocyte-derived MO3.13 cells. We screened a chemical library composed of drugs approved for central nervous system disorders that increased both the total intensity of PLP1A243V in the whole cell and the cell membrane localization. We analyzed the change in the endoplasmic reticulum (ER) stress and the gene expression of candidate chemicals using a micro-array analysis. Finally, we tested the in vivo effectiveness using myelin synthesis deficient (msd) mice with PlpA243V. Results and conclusion Piracetam significantly increased the PLP1A243V intensity and membrane localization and decreased the ER stress. It was also shown to reverse the gene expression changes induced by PLP1A243V in a micro-array analysis. However, in vivo treatment of piracetam did not improve the survival of msd mice (Plp1A243V).
Grace M Hobson - One of the best experts on this subject based on the ideXlab platform.
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Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes.
Human Mutation, 2020Co-Authors: Grace M Hobson, James Garbern, Edwin H. Kolodny, Erik A Sistermans, Zhong Huang, Karen Sperle, Peter K. Rogan, Sakkubai Naidu, Franca CambiAbstract:Mutations in the Proteolipid Protein 1 (PLP1) gene cause the X-linked dysmyelinating diseases Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia 2 (SPG2). We examined the severity of the following mutations that were suspected of affecting levels of PLP1 and DM20 RNA, the alternatively spliced products of PLP1: c.453G>A, c.453G>T, c.453G>C, c.453+2T>C, c.453+4A>G, c.347C>A, and c.453+28_+46del (the old nomenclature did not include the methionine codon: G450A, G450T, G450C, IVS3+2T>C, IVS3+4A>G, C344A, and IVS3+28-+46del). These mutations were evaluated by information theory-based analysis and compared with mRNA expression of the alternatively spliced products. The results are discussed relative to the clinical severity of disease. We conclude that the observed PLP1 and DM20 splicing patterns correlated well with predictions of information theory-based analysis, and that the relative strength of the PLP1 and DM20 donor splice sites plays an important role in PLP1 alternative splicing. Hum Mutat 27(1), 69–77, 2006. © 2005 Wiley-Liss, Inc.
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Morpholino Antisense Oligomers as a Potential Therapeutic Option for the Correction of Alternative Splicing in PMD, SPG2, and HEMS
Molecular therapy. Nucleic acids, 2018Co-Authors: Stephanie Tantzer, Karen Sperle, Kaitlin Kenaley, Jennifer R. Taube, Grace M HobsonAbstract:DNA variants of the Proteolipid Protein 1 gene (PLP1) that shift PLP1/DM20 alternative splicing away from the PLP1 form toward DM20 cause the allelic X-linked leukodystrophies Pelizaeus-Merzbacher disease (PMD), spastic paraplegia 2 (SPG2), and hypomyelination of early myelinating structures (HEMS). We designed a morpholino oligomer (MO-PLP) to block use of the DM20 5′ splice donor site, thereby shifting alternative splicing toward the PLP1 5′ splice site. Treatment of an immature oligodendrocyte cell line with MO-PLP significantly shifted alternative splicing toward PLP1 expression from the endogenous gene and from transfected human minigene splicing constructs harboring patient variants known to reduce the amount of the PLP1 spliced product. Additionally, a single intracerebroventricular injection of MO-PLP into the brains of neonatal mice, carrying a deletion of an intronic splicing enhancer identified in a PMD patient that reduces the Plp1 spliced form, corrected alternative splicing at both RNA and Protein levels in the CNS. The effect lasted to post-natal day 90, well beyond the early post-natal spike in myelination and PLP production. Further, the single injection produced a sustained reduction of inflammatory markers in the brains of the mice. Our results suggest that morpholino oligomers have therapeutic potential for the treatment of PMD, SPG2, and HEMS.
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Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes
American Journal of Human Genetics, 2017Co-Authors: Zachary S. Nevin, Grace M Hobson, Jeremy J Laukka, Martha S. Windrem, Steven A. Goldman, Daniel C. Factor, Robert T. Karl, Panagiotis Douvaras, Valentina Fossati, Paul J. TesarAbstract:Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene Proteolipid Protein 1 ( PLP1 ) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD—including point mutations and duplication, triplication, and deletion of PLP1 —and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.
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PMD patient mutations reveal a long-distance intronic interaction that regulates PLP1/DM20 alternative splicing
Human Molecular Genetics, 2014Co-Authors: Jennifer R. Taube, James Y. Garbern, Pavel Seeman, Karen Sperle, Linda Banser, Barbra Charina V. Cavan, Grace M HobsonAbstract:Alternative splicing of the Proteolipid Protein 1 gene (PLP1) produces two forms, PLP1 and DM20, due to alternative use of 5′ splice sites with the same acceptor site in intron 3. The PLP1 form predominates in central nervous system RNA. Mutations that reduce the ratio of PLP1 to DM20, whether mutant or normal Protein is formed, result in the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD). We investigated the ability of sequences throughout PLP1 intron 3 to regulate alternative splicing using a splicing minigene construct transfected into the oligodendrocyte cell line, Oli-neu. Our data reveal that the alternative splice of PLP1 is regulated by a long-distance interaction between two highly conserved elements that are separated by 581 bases within the 1071-base intron 3. Further, our data suggest that a base-pairing secondary structure forms between these two elements, and we demonstrate that mutations of either element designed to destabilize the secondary structure decreased the PLP1/DM20 ratio, while swap mutations designed to restore the structure brought the PLP1/DM20 ratio to near normal levels. Sequence analysis of intron 3 in families with clinical symptoms of PMD who did not have coding-region mutations revealed mutations that segregated with disease in three families. We showed that these patient mutations, which potentially destabilize the secondary structure, also reduced the PLP1/DM20 ratio. This is the first report of patient mutations causing disease by disruption of a long-distance intronic interaction controlling alternative splicing. This finding has important implications for molecular diagnostics of PMD.
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Gait Abnormalities and Progressive Myelin Degeneration in a New Murine Model of Pelizaeus-Merzbacher Disease with Tandem Genomic Duplication
The Journal of Neuroscience, 2013Co-Authors: Kristi A. Clark, Robert P. Skoff, Denise Bessert, Karen Sperle, Lauren Sakowski, Linda Banser, Carlisle P. Landel, Grace M HobsonAbstract:Pelizaeus-Merzbacher disease (PMD) is a hypomyelinating leukodystrophy caused by mutations of the Proteolipid Protein 1 gene (PLP1), which is located on the X chromosome and encodes the most abundant Protein of myelin in the central nervous sytem. Approximately 60% of PMD cases result from genomic duplications of a region of the X chromosome that includes the entire PLP1 gene. The duplications are typically in a head-to-tail arrangement, and they vary in size and gene content. Although rodent models with extra copies of Plp1 have been developed, none contains an actual genomic rearrangement that resembles those found in PMD patients. We used mutagenic insertion chromosome engineering resources to generate the Plp1dup mouse model by introducing an X chromosome duplication in the mouse genome that contains Plp1 and five neighboring genes that are also commonly duplicated in PMD patients. The Plp1dup mice display progressive gait abnormalities compared with wild-type littermates. The single duplication leads to increased transcript levels of Plp1 and four of the five other duplicated genes over wild-type levels in the brain beginning the second postnatal week. The Plp1dup mice also display altered transcript levels of other important myelin Proteins leading to a progressive degeneration of myelin. Our results show that a single duplication of the Plp1 gene leads to a phenotype similar to the pattern seen in human PMD patients with duplications.
Thomas D. Bird - One of the best experts on this subject based on the ideXlab platform.
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Neuronal loss in Pelizaeus–Merzbacher disease differs in various mutations of the Proteolipid Protein 1
Acta Neuropathologica, 2009Co-Authors: Anders A. F. Sima, Grace M Hobson, Christopher R. Pierson, Randall L. Woltjer, Jeffrey A. Golden, William J. Kupsky, Galen M. Schauer, Thomas D. Bird, Robert P. Skoff, James Y. GarbernAbstract:Mutations affecting Proteolipid Protein 1 (PLP1), the major Protein in central nervous system myelin, cause the X-linked leukodystrophy Pelizaeus–Merzbacher disease (PMD). We describe the neuropathologic findings in a series of eight male PMD subjects with confirmed PLP1 mutations, including duplications, complete gene deletion, missense and exon-skipping. While PLP1 mutations have effects on oligodendrocytes that result in mutation-specific degrees of dysmyelination, our findings indicate that there are also unexpected effects in the central nervous system resulting in neuronal loss. Although length-dependent axonal degeneration has been described in PLP1 null mutations, there have been no reports on neuronal degeneration in PMD patients. We now demonstrate widespread neuronal loss in PMD. The patterns of neuronal loss appear to be dependent on the mutation type, suggesting selective vulnerability of neuronal populations that depends on the nature of the PLP1 disturbance. Nigral neurons, which were not affected in patients with either null or severe misfolding mutations, and thalamic neurons appear particularly vulnerable in PLP1 duplication and deletion patients, while hippocampal neuronal loss was prominent in a patient with complete PLP1 gene deletion. All subjects showed cerebellar neuronal loss. The patterns of neuronal involvement may explain some clinical findings, such as ataxia, being more prominent in PMD than in other leukodystrophies. While the precise pathogenetic mechanisms are not known, these observations suggest that defective glial functions contribute to neuronal pathology.
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neuronal loss in pelizaeus merzbacher disease differs in various mutations of the Proteolipid Protein 1
Acta Neuropathologica, 2009Co-Authors: Anders A. F. Sima, Grace M Hobson, Christopher R. Pierson, Randall L. Woltjer, Jeffrey A. Golden, William J. Kupsky, Thomas D. Bird, Galen Schauer, Robert P. SkoffAbstract:Mutations affecting Proteolipid Protein 1 (PLP1), the major Protein in central nervous system myelin, cause the X-linked leukodystrophy Pelizaeus–Merzbacher disease (PMD). We describe the neuropathologic findings in a series of eight male PMD subjects with confirmed PLP1 mutations, including duplications, complete gene deletion, missense and exon-skipping. While PLP1 mutations have effects on oligodendrocytes that result in mutation-specific degrees of dysmyelination, our findings indicate that there are also unexpected effects in the central nervous system resulting in neuronal loss. Although length-dependent axonal degeneration has been described in PLP1 null mutations, there have been no reports on neuronal degeneration in PMD patients. We now demonstrate widespread neuronal loss in PMD. The patterns of neuronal loss appear to be dependent on the mutation type, suggesting selective vulnerability of neuronal populations that depends on the nature of the PLP1 disturbance. Nigral neurons, which were not affected in patients with either null or severe misfolding mutations, and thalamic neurons appear particularly vulnerable in PLP1 duplication and deletion patients, while hippocampal neuronal loss was prominent in a patient with complete PLP1 gene deletion. All subjects showed cerebellar neuronal loss. The patterns of neuronal involvement may explain some clinical findings, such as ataxia, being more prominent in PMD than in other leukodystrophies. While the precise pathogenetic mechanisms are not known, these observations suggest that defective glial functions contribute to neuronal pathology.
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Patients lacking the major CNS myelin Protein, Proteolipid Protein 1, develop length‐dependent axonal degeneration in the absence of demyelination and inflammation
Brain, 2002Co-Authors: James Garbern, D A Yool, Gregory J Moore, Ian B Wilds, Michael W Faulk, Matthias Klugmann, Klausarmin Nave, Erik A Sistermans, M S Van Der Knaap, Thomas D. BirdAbstract:Axonal degeneration contributes to clinical disability in the acquired demyelinating disease multiple sclerosis. Axonal degeneration occurs during acute attacks, associated with inflammation, and during the chronic progressive phase of the disease in which inflammation is not prominent. To explore the importance of interactions between oligodendrocytes and axons in the CNS, we analysed the brains of rodents and humans with a null mutation in the gene encoding the major CNS myelin Protein, Proteolipid Protein (PLP1, previously PLP). Histological analyses of the CNS of Plp1 null mice and of autopsy material from patients with null PLP1 mutations were performed to evaluate axonal and myelin integrity. In vivo proton magnetic resonance spectroscopy (MRS) of PLP1 null patients was conducted to measure levels of N ‐acetyl aspartate (NAA), a marker of axonal integrity. Length‐dependent axonal degeneration without demyelination was identified in the CNS of Plp1 null mice. Proton MRS of PLP1‐deficient patients showed reduced NAA levels, consistent with axonal loss. Analysis of patients’ brain tissue also demonstrated a length‐dependent pattern of axonal loss without significant demyelination. Therefore, axonal degeneration occurs in humans as well as mice lacking the major myelin Protein PLP1. This degeneration is length‐dependent, similar to that found in the PNS of patients with the inherited demyelinating neuropathy, CMT1A, but is not associated with significant demyelination. Disruption of PLP1‐mediated axonal–glial interactions thus probably causes this axonal degeneration. A similar mechanism may be responsible for axonal degeneration and clinical disability that occur in patients with multiple sclerosis.
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patients lacking the major cns myelin Protein Proteolipid Protein 1 develop length dependent axonal degeneration in the absence of demyelination and inflammation
Brain, 2002Co-Authors: James Garbern, D A Yool, Gregory J Moore, Ian B Wilds, Michael W Faulk, Matthias Klugmann, Klausarmin Nave, Erik A Sistermans, M S Van Der Knaap, Thomas D. BirdAbstract:Axonal degeneration contributes to clinical disability in the acquired demyelinating disease multiple sclerosis. Axonal degeneration occurs during acute attacks, associated with inflammation, and during the chronic progressive phase of the disease in which inflammation is not prominent. To explore the importance of interactions between oligodendrocytes and axons in the CNS, we analysed the brains of rodents and humans with a null mutation in the gene encoding the major CNS myelin Protein, Proteolipid Protein (PLP1, previously PLP). Histological analyses of the CNS of Plp1 null mice and of autopsy material from patients with null PLP1 mutations were performed to evaluate axonal and myelin integrity. In vivo proton magnetic resonance spectroscopy (MRS) of PLP1 null patients was conducted to measure levels of N ‐acetyl aspartate (NAA), a marker of axonal integrity. Length‐dependent axonal degeneration without demyelination was identified in the CNS of Plp1 null mice. Proton MRS of PLP1‐deficient patients showed reduced NAA levels, consistent with axonal loss. Analysis of patients’ brain tissue also demonstrated a length‐dependent pattern of axonal loss without significant demyelination. Therefore, axonal degeneration occurs in humans as well as mice lacking the major myelin Protein PLP1. This degeneration is length‐dependent, similar to that found in the PNS of patients with the inherited demyelinating neuropathy, CMT1A, but is not associated with significant demyelination. Disruption of PLP1‐mediated axonal–glial interactions thus probably causes this axonal degeneration. A similar mechanism may be responsible for axonal degeneration and clinical disability that occur in patients with multiple sclerosis.
Christian Beste - One of the best experts on this subject based on the ideXlab platform.
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PLP1 Gene Variation Modulates Leftward and Rightward Functional Hemispheric Asymmetries
Molecular Neurobiology, 2018Co-Authors: Sebastian Ocklenburg, Wanda M Gerding, Larissa Arning, Erhan Genc, Jorg T Epplen, Onur Gunturkun, Maximilian Raane, Christian BesteAbstract:Molecular neurobiological factors determining corpus callosum physiology and anatomy have been suggested to be one of the major factors determining functional hemispheric asymmetries. Recently, it was shown that allelic variations in two myelin-related genes, the Proteolipid Protein 1 gene PLP1 and the contactin 1 gene CNTN1 , are associated with differences in interhemispheric integration. Here, we investigated whether three single nucleotide polymorphisms that were associated with interhemispheric integration via the corpus callosum in a previous study also are relevant for functional hemispheric asymmetries. To this end, we tested more than 900 healthy adults with the forced attention dichotic listening task, a paradigm to assess language lateralization and its modulation by cognitive control processes. Moreover, we used the line bisection task, a paradigm to assess functional hemispheric asymmetries in spatial attention. We found that a polymorphism in PLP1 , but not CNTN1 , was associated with performance differences in both tasks. Both functional hemispheric asymmetries and their modulation by cognitive control processes were affected. These findings suggest that both left and right hemisphere dominant cognitive functions can be modulated by allelic variation in genes affecting corpus callosum structure. Moreover, higher order cognitive processes may be relevant parameters when investigating the molecular basis of hemispheric asymmetries.
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myelin genes and the corpus callosum Proteolipid Protein 1 plp1 and contactin 1 cntn1 gene variation modulates interhemispheric integration
Molecular Neurobiology, 2017Co-Authors: Sebastian Ocklenburg, Wanda M Gerding, Larissa Arning, Erhan Genc, Jorg T Epplen, Onur Gunturkun, Christian BesteAbstract:Interhemispheric communication during demanding cognitive tasks shows pronounced interindividual variation. Differences in interhemispheric transfer time are constituted by the relative composition of slow and fast fibers. The speed of axonal conduction depends on the diameter of the axon and its myelination. To understand the possible genetic impact of myelin genes on performance in the Banich-Belger Task, a widely used paradigm to assess interhemispheric integration, 453 healthy adults were genotyped for 18 single nucleotide polymorphisms (SNPs) in six myelin-related candidate genes. We replicated the typical pattern of results in the Banich-Belger Task, supporting the idea that performance on cognitively demanding tasks is enhanced when cognitive processing is distributed across the two hemispheres. Moreover, allelic variations in the Proteolipid Protein 1 gene PLP1 and the contactin 1 gene CNTN1 correlated with the extent to which individual performance is enhanced by interhemispheric integration. Variation in myelin genes possibly affects the microstructure of the corpus callosum by altering oligodendrocyte structure. Therefore, these results provide a foundation for understanding how genetics plays a role in modulating the efficacy of transcallosal transmission.
