Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder.

Hudson, Lynn D.; Puckett, Carmie; Berndt, Jo Ann; Chan, Jennifer A.; Gencic, Simonida

doi:10.1073/pnas.86.20.8128

Cited by 182 publications

(100 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Most of the missense mutations studied to date disrupt the trafficking of PLP to the cell surface (Gow et al, 1994b;Gow and Lazzarini, 1996;Woodward, 2008), and it is generally believed that the pathogenic mechanism underlying PMD is the accumulation of misfolded PLP in the ER leading to activation of the UPR and oligodendrocyte apoptosis (Gow and Lazzarini, 1996;Gow et al, 1998;Southwood et al, 2002). However, the disease caused by missense mutations can range in phenotypic severity from mild PMD and late-onset spastic paraplegia type 2 (SPG2), which is characterised by hypomyelination and thinning of the myelin sheath (Hodes et al, 1997;Kobayashi et al, 1994), to severe connatal PMD associated with widespread oligodendrocyte apoptosis and a virtual absence of compact myelin Hudson et al, 1989). The critical factors that determine whether a particular mutation of the gene encoding PLP gives rise to a mild disease with hypomyelination or a severe disease with oligodendrocyte apoptosis are currently poorly understood (Dhaunchak and Nave, 2007;Gow and Lazzarini, 1996;Gow et al, 1998;Kramer-Albers et al, 2006;Southwood and Gow, 2001).…”

Section: Introductionmentioning

confidence: 99%

Differences in endoplasmic-reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein

Roboti

Swanton

High

2009

Journal of Cell Science

View full text Add to dashboard Cite

Missense mutations in human PLP1, the gene encoding myelin proteolipid protein (PLP), cause dysmyelinating PelizaeusMerzbacher disease of varying severity. Although disease pathology has been linked to retention of misfolded PLP in the endoplasmic reticulum (ER) and induction of the unfolded protein response (UPR), the molecular mechanisms that govern phenotypic heterogeneity remain poorly understood. To address this issue, we examined the cellular response to missense mutants of PLP that are associated with distinct disease phenotypes. We found that the mild-disease-associated mutants, W162L and G245A, were cleared from the ER comparatively quickly via proteasomal degradation and/or ER exit. By contrast, the more 'aggressive' A242V mutant, which causes severe disease, was significantly more stable, accumulated at the ER and resulted in a specific activation of the UPR. On the basis of these findings, we propose that the rate at which mutant PLP proteins are cleared from the ER modulates disease severity by determining the extent to which the UPR is activated. Supplementary material available online at

show abstract

Section: Introductionmentioning

confidence: 99%

Differences in endoplasmic-reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein

Roboti

Swanton

High

2009

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…PLP peptide 190-209 (SKTSASIGSLCADARMYGVL) was synthesised by Auspep (Melbourne, Australia) according to the human sequence (Hudson et al, 1989) and was >95% pure by high performance liquid chromatography and mass spectral analysis. This peptide is moderately hydrophobic and was dissolved at a concentration of 5 mg/mL in 0.2 M acetic acid prior to dilution in phosphate-buffered saline (PBS).…”

Section: Plp Peptidementioning

confidence: 99%

Blood–brain barrier disruption and lesion localisation in experimental autoimmune encephalomyelitis with predominant cerebellar and brainstem involvement

Muller

Pender

Greer

2005

Journal of Neuroimmunology

View full text Add to dashboard Cite

The role of the blood-brain barrier (BBB) in determining lesion distribution was assessed in an atypical model of experimental autoimmune encephalomyelitis (EAE) induced in C3H/HeJ mice by immunisation with peptide 190-209 of myelin proteolipid protein, which can result in two distinct types of EAE, each with distinct lesion distribution. Areas of the BBB showing constitutively greater permeability in naïve mice did not correlate with the lesion distribution in EAE. BBB disruption occurred only in sites of inflammatory cell infiltration. Irrespective of the clinical type, the BBB was disrupted in the cerebellum and brainstem. Pertussis toxin had no effect on lesion distribution. Thus, lesion distribution is not influenced solely by BBB permeability.

show abstract

“…PLP peptides PLP peptide 190-209 (SKTSASIGSLCADARMYGVL) was synthesized by Auspep (Melbourne, Australia) according to the human sequence [13] and was greater than 95% pure by high performance liquid chromatography (HPLC) and mass spectral analysis. This peptide is moderately hydrophobic and was dissolved at a concentration of 5 mg/ml in 0.2 M acetic acid prior to dilution in phosphate-buffered saline (PBS) or tissue culture medium.…”

Section: Micementioning

confidence: 99%

A neuropathological analysis of experimental autoimmune encephalomyelitis with predominant brain stem and cerebellar involvement and differences between active and passive induction

Muller

Pender

Greer

2000

Acta Neuropathologica

View full text Add to dashboard Cite

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune demyelinating disease that can be induced in a variety of animal species and which is commonly used as an animal model of multiple sclerosis. In rodent EAE models, the clinical disease is typified by ascending paralysis; however, other clinical patterns can also be observed by inducing disease with particular peptides of myelin proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein. Here we describe EAE induced in C3H/HeJ mice by inoculation with residues 190-209 of PLP. This form of EAE is manifested clinically by a movement disorder, with axial rotation of the head and trunk. Histologically, this form of EAE is characterized by predominant cerebellar or brain stem involvement, depending on whether EAE is induced by active immunization with the PLP peptide, or by passive transfer of T cells specific for the peptide. The inflammatory cell infiltrate is composed of polymorphonuclear cells and mononuclear cells. This rotatory form of EAE may be a useful model for studying the neuropathological characteristics of multiple sclerosis affecting the brain stem and cerebellum.

show abstract

Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder.

Abstract: Myelin is a highly specialized membrane unique to the nervous system that ensheaths axons to permit the rapid saltatory conduction of impulses. The elaboration of a compact myelin sheath is disrupted in a diverse spectrum of human disorders, many of which are of unknown etiology. The

Cited by 182 publications

References 33 publications

Differences in endoplasmic-reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein

Differences in endoplasmic-reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein

Blood–brain barrier disruption and lesion localisation in experimental autoimmune encephalomyelitis with predominant cerebellar and brainstem involvement

A neuropathological analysis of experimental autoimmune encephalomyelitis with predominant brain stem and cerebellar involvement and differences between active and passive induction

Contact Info

Product

Resources

About