Assembly of CNS Myelin in the Absence of Proteolipid Protein

Klugmann, Matthias; Schwab, Markus H.; Pühlhofer, Anja; Schneider, Armin; Zimmermann, Frank; Griffiths, I. R.; Nave, Klaus Armin

doi:10.1016/s0896-6273(01)80046-5

Cited by 419 publications

(434 citation statements)

References 57 publications

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“…2,13,17 Indeed, knockout mice with a functionally null Plp1 gene do not develop classical signs of Plp1-related disease; their oligodendrocytes develop normally and synthesize compact myelin sheaths. 3,18 However, the mice show ultrastructural abnormalities, including swelling of the small-diameter axons and late-onset axonal degeneration. 3,19 Consequently, a loss-of-function mutation of PLP1 does not induce oligodendrocyte cell death, possibly serving as a mechanism underlying the milder phenotypic consequences observed in patients with null PLP1 mutations.…”

Section: Discussionmentioning

confidence: 99%

Reduced PLP1 expression in induced pluripotent stem cells derived from a Pelizaeus–Merzbacher disease patient with a partial PLP1 duplication

et al. 2012

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Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder characterized by dysmyelination of the central nervous system (CNS). We identified a rare partial duplication of the proteolipid protein 1 gene (PLP1) in a patient with PMD. To assess the underlying effect of this duplication, we examined PLP1 expression in induced pluripotent stem (iPS) cells generated from the patient's fibroblasts. Disease-specific iPS cells were generated from skin fibroblasts obtained from the indicated PMD patient and two other PMD patients having a 637-kb chromosomal duplication including entire PLP1 and a novel missense mutation (W212C) of PLP1, by transfections of OCT3/4, C-MYC, KLF4 and SOX2 using retro-virus vectors. PLP1 expressions in the generated iPS cells were examined by northern blot analysis. Although PLP1 expression was confirmed in iPS cells generated from two patients with the entire PLP1 duplication and the missense mutation of PLP1, iPS cells generated from the patient with the partial PLP1 duplication manifesting a milder form of PMD showed null expression. This indicated that the underlying effect of the partial PLP1 duplication identified in this study was different from other PLP1 alterations including a typical duplication and a missense mutation.

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Section: Discussionmentioning

confidence: 99%

Reduced PLP1 expression in induced pluripotent stem cells derived from a Pelizaeus–Merzbacher disease patient with a partial PLP1 duplication

et al. 2012

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“…9 This model suggests that the severe impairment in the achievement of normal milestones during the first year of life that distinguishes PMD from SPG may result from a deficit in the number of mature oligodendrocytes, the severity of PMD being correlated with the number of surviving oligodendrocytes. [27][28][29][30] The cellular events responsible for differences in the survival of myelinating oligodendrocytes are unknown. The mechanisms by which abnormal PLP products may be deleterious to the cell include the loss of normal function, a gain of function in which the altered protein becomes cytotoxic, and perturbation of intracellular trafficking in oligodendrocytes.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations

et al. 2000

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Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2) are X-linked developmental defects of myelin formation affecting the central nervous system (CNS). They differ clinically in the onset and severity of the motor disability but both are allelic to the proteolipid protein gene (PLP), which encodes the principal protein components of CNS myelin, PLP and its spliced isoform, DM20. We investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by genomic PCR amplification and sequencing of the PLP gene. We identified 29 and 4 abnormalities respectively. Patients with PLP mutations presented a large range of disease severity, with a continuum between severe forms of PMD, without motor development, to pure forms of SPG. Clinical severity was found to be correlated with the nature of the mutation, suggesting a distinct strategy for detection of PLP point mutations between severe PMD, mild PMD and SPG. Single amino-acid changes in highly conserved regions of the DM20 protein caused the most severe forms of PMD. Substitutions of less conserved amino acids, truncations, absence of the protein and PLP-specific mutations caused the milder forms of PMD and SPG. Therefore, the interactions and stability of the mutated proteins has a major effect on the severity of PLP-related diseases.

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“…PLP À/À mice were obtained from Klaus-Armin Nave (Max-Planck Institute of Experimental Medicine, Göttingen, Germany) (Klugmann et al, 1997) and were bred onto the SJL background. (SJL 3 B10.BR)F 1 mice were bred at The Children's Hospital of Philadelphia Laboratory Animal Facility.…”

Section: Micementioning

confidence: 99%

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species

Greenfield¹,

Reddy²,

Lees³

et al. 2006

J of Neuroscience Research

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Myelin proteolipid protein (PLP), the major protein of mammalian CNS myelin, is a member of the proteolipid gene family (pgf). It is an evolutionarily conserved polytopic integral membrane protein and a potential autoantigen in multiple sclerosis (MS). To analyze antibody recognition of PLP epitopes in situ, monoclonal antibodies (mAbs) specific for different regions of human PLP (50–69, 100–123, 139–151, 178–191, 200–219, 264–276) were generated and used to immunostain CNS tissues of representative vertebrates. mAbs to each region recognized whole human PLP on Western blots; the anti‐100–123 mAb did not recognize DM‐20, the PLP isoform that lacks residues 116–150. All of the mAbs stained fixed, permeabilized oligodendrocytes and mammalian and avian CNS tissue myelin. Most of the mAbs also stained amphibian, teleost, and elasmobranch CNS myelin despite greater diversity of their pgf myelin protein sequences. Myelin staining was observed when there was at least 40% identity of the mAb epitope and known pgf myelin proteins of the same or related species. The pgf myelin proteins of teleosts and elasmobranchs lack 116–150; the anti‐100–123 mAb did not stain their myelin. In addition to myelin, the anti‐178–191 mAb stained many neurons in all species; other mAbs stained distinct neuron subpopulations in different species. Neuronal staining was observed when there was at least approximately 30% identity of the PLP mAb epitope and known pgf neuronal proteins of the same or related species. Thus, anti‐human PLP epitope mAbs simultaneously recognize CNS myelin and neurons even without extensive sequence identity. Widespread anti‐PLP mAb recognition of neurons suggests a novel potential pathophysiologic mechanism in MS patients, i.e., that anti‐PLP antibodies associated with demyelination might simultaneously recognize pgf epitopes in neurons, thereby affecting their functions. © 2006 Wiley‐Liss, Inc.

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Assembly of CNS Myelin in the Absence of Proteolipid Protein

Cited by 419 publications

References 57 publications

Reduced PLP1 expression in induced pluripotent stem cells derived from a Pelizaeus–Merzbacher disease patient with a partial PLP1 duplication

Reduced PLP1 expression in induced pluripotent stem cells derived from a Pelizaeus–Merzbacher disease patient with a partial PLP1 duplication

Genotype–phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species

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