An update on the leukodsytrophies

Schiffmann, Raphael; Boespflug‐Tanguy, Odile

doi:10.1097/00019052-200112000-00018

Cited by 47 publications

(21 citation statements)

References 45 publications

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“…n ϭ 12 for PLP 4 h plus 8 h, n ϭ 8 for DM20 4 h plus 8 h, n ϭ 3 for PLP plus DM20 24 h. more aggressive msd-PLP was degraded even faster than rsh-PLP. This is in agreement with in vivo studies, which suggest limited accumulation of mutant PLP/DM20 in the cell bodies of oligodendrocytes (Schiffmann and Boespflug-Tanguy, 2001). Increased turnover of rsh-PLP/DM20 has also been observed recently in primary oligodendrocytes isolated from rsh mice (McLaughlin et al, 2006).…”

Section: Turnover and Proteasomal Degradation Of Mutant Plp/dm20supporting

confidence: 92%

Perturbed Interactions of Mutant Proteolipid Protein/DM20 with Cholesterol and Lipid Rafts in Oligodendroglia: Implications for Dysmyelination in Spastic Paraplegia

Krämer-Albers¹,

Gehrig‐Burger²,

Thiele³

et al. 2006

J. Neurosci.

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Missense mutations in the human PLP1 gene lead to dysmyelinating diseases with a broad range of clinical severity, ranging from severe Pelizaeus-Merzbacher disease (PMD) to milder spastic paraplegia type 2 (SPG-2). The molecular pathology has been generally attributed to endoplasmic reticulum (ER) retention of misfolded proteolipid protein (PLP) (and its splice isoform DM20) and induction of the unfolded protein response. As opposed to previous studies of heterologous expression systems, we have analyzed PLP/DM20 trafficking in oligodendroglial cells, thereby revealing differences between PMD and SPG-2-associated PLP/DM20 isoforms. PLP A242V and DM20 A242V ( jimpy-msd in mice), associated with severe PMD-like phenotype in vivo, were not only retained in the ER but also interfered with oligodendroglial process formation. In contrast, glial cells expressing SPG-2-associated PLP I186T or DM20 I186T (rumpshaker in mice) developed processes, and mutant PLP/DM20 reached a late endosomal/lysosomal compartment. Unexpectedly, PLP/DM20 with either substitution exhibited impaired cholesterol binding, and the association with lipid raft microdomains was strongly reduced. Turnover analysis demonstrated that mutant PLP was rapidly degraded in oligodendroglial cells, with half-lives for PLP Ͼ PLP I186T Ͼ PLP A242V . Protein degradation was specifically sensitive to proteasome inhibition, although PLP/DM20I186T degradation was also affected by inhibition of lysosomal enzymes. We conclude that, in addition to ER retention and unfolded protein response (UPR) induction, impaired cholesterol binding and lipid raft association are characteristic cellular defects of PLP1-missense mutations. Mutant protein is rapidly cleared and does not accumulate in oligodendroglial cells. Whereas UPR-induced cell death governs the PMD phenotype of the msd mutation, we propose that impaired cholesterol and lipid raft interaction of the rsh protein may contribute to the dysmyelination observed in SPG-2.

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Section: Turnover and Proteasomal Degradation Of Mutant Plp/dm20supporting

confidence: 92%

Perturbed Interactions of Mutant Proteolipid Protein/DM20 with Cholesterol and Lipid Rafts in Oligodendroglia: Implications for Dysmyelination in Spastic Paraplegia

Krämer-Albers¹,

Gehrig‐Burger²,

Thiele³

et al. 2006

J. Neurosci.

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“…Several diseases in humans disrupt normal CNS myelin, such as Canavan's disease, Pelizaeus-Merzbacher disease, and multiple sclerosis (Schiffmann and Boespflug-Tanguy, 2001;Franklin, 2002;Surendran et al, 2003). Although gene mutations that cause the first two of these have been identified, the gene loci that govern MS susceptibility are still unknown.…”

Section: Association Of Genes Regulated During Oligodendrocyte Differmentioning

confidence: 99%

Functional Genomic Analysis of Oligodendrocyte Differentiation

Dugas¹,

Tai²,

Speed³

et al. 2006

J. Neurosci.

294

353

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To better understand the molecular mechanisms governing oligodendrocyte (OL) differentiation, we have used gene profiling to quantitatively analyze gene expression in synchronously differentiating OLs generated from pure oligodendrocyte precursor cells in vitro. By comparing gene expression in these OLs to OLs generated in vivo, we discovered that the program of OL differentiation can progress normally in the absence of heterologous cell-cell interactions. In addition, we found that OL differentiation was unexpectedly prolonged and occurred in at least two sequential stages, each characterized by changes in distinct complements of transcription factors and myelin proteins. By disrupting the normal dynamic expression patterns of transcription factors regulated during OL differentiation, we demonstrated that these sequential stages of gene expression can be independently controlled. We also uncovered several genes previously uncharacterized in OLs that encode transmembrane, secreted, and cytoskeletal proteins that are as highly upregulated as myelin genes during OL differentiation. Last, by comparing genomic loci associated with inherited increased risk of multiple sclerosis (MS) to genes regulated during OL differentiation, we identified several new positional candidate genes that may contribute to MS susceptibility. These findings reveal a previously unexpected complexity to OL differentiation and suggest that an intrinsic program governs successive phases of OL differentiation as these cells extend and align their processes, ensheathe, and ultimately myelinate axons.

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“…Some progression of myelination is observed until 12 years of age [9]. The second decade is marked by neurological deterioration with cortico-subcortical atrophy on MRI, leading to severe quadriplegia, amyotrophy, optic atrophy, and cognitive decline in young adults, even in the mildest forms [10]. Several recent studies have underlined the correlation between clinical severity and brain atrophy on MRI [9,11,12].…”

Section: Introductionmentioning

confidence: 99%

Brain Diffusion Imaging and Tractography to Distinguish Clinical Severity of Human <b><i>PLP1</i></b>-Related Disorders

et al. 2018

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Aims: We performed quantitative diffusion tensor imaging and brain tractography to distinguish clinical severity in a series of 35 patients with hypomyelinating PLP1-related disorders classified using the Motor Developmental Score according to the best motor function acquired before the age of 5 years and the gross motor function measure (GMFM) at the time of magnetic resonance imaging acquisition. Methods: We calculated fractional anisotropy and diffusivity values in 26 regions of interest and the numbers of fibers and volumes of hemisphere tractograms. Fiber bundles on tractograms were characterized according to 3 criteria: size, direction of main-stream fibers, and connectivity of bundles (extratelencephalic projections, commissural fibers, and intrahemispheric connections). Results: Age-adjusted multivariate analysis in 3 severity groups revealed increased isotropic diffusion in the superior cerebellar peduncle and grey matter in the most severe group, and larger tractogram volumes and increased numbers of fibers in the least severely affected group. Tractogram patterns showed preserved extratelencephalic projections and a main anterior-posterior aspect of intrahemispheric fibers in most patients, whereas interhemispheric connectivity was variable. The most severely affected and intermediate patients had less intrahemispheric connectivity, with a frequent predominant anterior-posterior direction of main-stream fibers. Interpretation: Diffusion tensor imaging and tractographic parameters can operate as biomarkers to distinguish clinical severity in PLP1-related disorders and could improve our understanding of hypomyelinating leukodystrophies.

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An update on the leukodsytrophies

Cited by 47 publications

References 45 publications

Perturbed Interactions of Mutant Proteolipid Protein/DM20 with Cholesterol and Lipid Rafts in Oligodendroglia: Implications for Dysmyelination in Spastic Paraplegia

Perturbed Interactions of Mutant Proteolipid Protein/DM20 with Cholesterol and Lipid Rafts in Oligodendroglia: Implications for Dysmyelination in Spastic Paraplegia

Functional Genomic Analysis of Oligodendrocyte Differentiation

Brain Diffusion Imaging and Tractography to Distinguish Clinical Severity of Human <b><i>PLP1</i></b>-Related Disorders

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