Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis

Garbern, James

doi:10.1007/s00018-006-6182-8

Cited by 162 publications

(159 citation statements)

References 166 publications

(222 reference statements)

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“…For example, the daily amount of protein synthesized at the peak of myelination in a single OL myelinating multiple axonal segments can be up to three times the weight of its perikaryon [29] . Even when myelination is completed, mature OLs continuously require a high energy supply for the maintenance of their lipid-rich myelin membrane.…”

Section: Discussionmentioning

confidence: 99%

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

Wang

et al. 2013

Neurosci. Bull.

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Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

Wang

et al. 2013

Neurosci. Bull.

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“…Patient 3 showed a novel missense mutation, c.636G4C (Tyr212Cys), which is in the extramembrane region of the PLP1 protein. 2 A missense substitution in the same codon, but resulting in a change into a different amino acid, c.634T4C (Tyr212Arg), has been reported to be a pathogenetic mutation by others. 13 Frequently, a cysteine residue changes the three-dimensional protein conformation drastically owing to disulfide bond formation with other cysteines.…”

Section: Discussionmentioning

confidence: 99%

“…Previous genotype-phenotype correlation study have shown that patients with PLP1 missense mutations show severe manifestation associated with severe hypomyelination, which is recognized as the consequence of accumulated mutant protein in the endoplasmic reticulum as a gain-of-toxic function of the mutant protein. 2 Excessive PLP1 protein resulting from genomic duplications may accumulate in late endosomes/lysosomes, promoting its incorporation into other myelin components. 1 In contrast, patients with PLP1 null mutations escape severe impairments because of the absence of any gain-of-toxic function.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with PMD often present with nystagmus as the initial symptom, and psychomotor developmental delay associated with spasticity and ataxia is seen later in development. [1][2][3] The proteolipid protein 1 gene (PLP1; MIM #300401), located on chromosome Xq22.2, is the gene responsible for PMD. It encodes 2 isoforms, PLP1 and DM20, as a consequence of differential splicing of exon 3.…”

Section: Introductionmentioning

confidence: 99%

“…The nucleotide alterations in PLP1 are varied and are scattered along the entire coding region of PLP1. [1][2][3] Because PLP1 is mainly expressed in oligodendrocytes in the CNS and cultured skin fibroblasts express low levels of PLP1, gene expression in the fibroblasts has been analyzed by comparative reverse-transcription (RT)-PCR analysis. 4,5 The use of technology to establish induced pluripotent stem (iPS) cells has now made it possible to examine gene expression and function in greater detail.…”

Section: Introductionmentioning

confidence: 99%

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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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A Novel Duplication Confirms the Involvement of 5q23.2 in Autosomal Dominant Leukodystrophy

Meijer

Simoes-Lopes²,

Laurent³

et al. 2008

Arch Neurol

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To identify the underlying locus and diseasecausing mutation for adult-onset autosomal dominant leukodystrophy (ADLD).Design: Previously, an adult-onset ADLD locus on chromosome 5q23 was mapped between markers D5S1495 and CTT/CCT15. This region contains 13 known and putative candidate genes. A 2-point linkage analysis confirmed linkage of a large multigenerational French Canadian family to chromosome 5q23. In addition, screening of the 13 genes within the candidate interval as well as 5 neighboring genes was completed, followed by comparative genomic hybridization.Subjects: A multigenerational French Canadian family with ADLD mimicking progressive multiple sclerosis was identified and studied. Eight affected family members were available for the study and presented with autonomic dysfunction as well as upper motorneuron signs affecting gait. Results:The thorough candidate gene approach did not identify any mutation. Consequently, a whole-chromosome comparative genomic hybridization for chromosome 5 identified a 280-kilobase duplication within the chromosomal band 5q23.2 in 2 affected individuals. This duplication contains 3 genes: LMNB1, FLJ36242, and MARCH3. Conclusion:We have identified a novel duplication on chromosomal band 5q23.2 in a French Canadian family with ADLD that supports the implication of duplicated LMNB1 as the disease-causing mutation. However, additional functional studies of lamin B1 overexpression are necessary to elucidate the involvement of lamin B1 in myelination and in degenerative disorders such as ADLD and multiple sclerosis.

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Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis

Cited by 162 publications

References 166 publications

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

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

A Novel Duplication Confirms the Involvement of 5q23.2 in Autosomal Dominant Leukodystrophy

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