Disease relevance of PLP1

• We describe genomic structures of 59 X-chromosome segmental duplications that include the proteolipid protein 1 gene (PLP1) in patients with Pelizaeus-Merzbacher disease [1].
• Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect [2].
• As shown previously, all patients with PLP1 null mutations had peripheral neuropathy [3].
• Primary progressive multiple sclerosis as a phenotype of a PLP1 gene mutation [4].
• To date, two of the MHV replicase-encoded proteinases, papain-like proteinase 1 (PLP1) and the poliovirus 3C-like proteinase (3CLpro), have been shown to process the replicase polyprotein [5].

Psychiatry related information on PLP1

• This report extends the phenotypic range of disease due to PLP gene mutations to include adult-onset dementia in females [6].
• We found robust activations in cortical motor areas [areas 4a, 4p, 6; dorsal premotor cortex (PMD) and bilateral supplementary motor area (SMA)] and ipsilateral cerebellum during kinesthetic illusions (illusion-vibration) [7].
• These studies have focused primarily on schizophrenia, and less so on the affective psychoses, including psychotic major depression PMD [8].
• We tested whether periodic maternal deprivation (180 min daily on postnatal days 3-10, PMD) caused chronic changes in emotional behavior and HPA axis activity in either male or female adult rats, or both [9].
• We have proposed a three-class hierarchical specificity model for sub-typing the depressive disorders (comprising psychotic, melancholic and non-melancholic depression), with specificity referring to two clinical features (psychotic symptoms and psychomotor disturbance or PMD) separating the first two classes from a residual non-melancholic class [10].

High impact information on PLP1

• Pelizaeus-Merzbacher disease (PMD) is a leukodystrophy linked to the proteolipid protein gene (PLP) [11].
• Classical PMD mutations correlate with accumulation of PLP in the ER of transfected COS-7 cells while the cognate DM20 traverses the secretory pathway to the cell surface [11].
• Defective metabolism of pyridoxal 5'-phosphate (PLP), characterized by elevated serum PLP levels, results in reduced levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain [12].
• A rare X-linked dysmyelinating disorder of the central nervous system, Pelizaeus-Merzbacher disease (PMD), has also been mapped to Xq21-q22, and is caused by mutations in the proteolipid protein gene (PLP) which encodes two myelin proteins, PLP and DM20 [13].
• We have found that a point mutation (His139Tyr) in exon 3B of an affected male produces a mutant PLP but a normal DM20, and segregates with the disease (Zmax = 6.63, theta = 0.00) [13].

Chemical compound and disease context of PLP1

• Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid [14].
• Brain N-acetylaspartate is elevated in Pelizaeus-Merzbacher disease with PLP1 duplication [15].
• Similarly, increased myelin expression was seen in brain sections from hypothermia plus NAC group, when stained for Luxol Fast Blue (LFB), Myelin Basic Protein (MBP) and Proteolipid protein (PLP) [16].
• The plasma PLP level was measured before and sequentially after the rapid intravenous administration of 50 mg of pyridoxine to patients with alcoholic cirrhosis, acute hepatitis, and extrahepatic obstruction, and to normal control subjects [17].
• In this report, we demonstrate that culture conditions that induce oligodendrocyte differentiation of glial progenitor cells also induce differentiation of C6 glioblastoma cells, as monitored by activated transcription of the gene encoding proteolipid protein (PLP), the major myelin protein of the CNS [18].

Biological context of PLP1

• Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females [19].
• PLP1 on the 19qtel is probably inactive by virtue of a position effect, because a healthy male sibling carries the same der(19) chromosome along with a normal X chromosome [19].
• Six PLP1 point mutations predicted to produce proteins with an intact PLP1-specific domain do not cause peripheral neuropathy [3].
• METHODS: Pulsed-field gel electrophoresis, custom array comparative genomic hybridization, and semi-quantitative multiplex polymerase chain reaction analyses were used to examine the PLP1 genomic region [2].
• INTERPRETATION: We propose the duplication to result in PLP1 gene silencing by virtue of a position effect [2].

Anatomical context of PLP1

• Proteolipid protein (PLP1) and its alternatively spliced isoform, DM20, are the major myelin proteins in the CNS, but are also expressed in the PNS [3].
• Sixty-one individuals with PLP1 duplications also had normal peripheral nerve function [3].
• PCR analysis of fibroblast cDNA showed that c.762G>T resulted in partial skipping of exon 6 in the PLP1 mRNA [20].
• The non-classic PLP/DM20 gene products appear to be components of intracellular transport vesicles in oligodendrocytes [21].
• Surges of increased T cell reactivity to an encephalitogenic region of myelin proteolipid protein occur more often in patients with multiple sclerosis than in healthy subjects [22].

Associations of PLP1 with chemical compounds

• These data demonstrate that expression of PLP1 but not DMSO is necessary to prevent neuropathy, and suggest that the 35 amino acid PLP1-specific domain plays an important role in normal peripheral nerve function [3].
• When myelin or white matter was extracted with chloroform/methanol, it contained, in addition to PLP, a significant amount of plasmolipin [23].
• Lipid analysis revealed that the PLP-MBP-S-MAG coimmunoprecipitated with some phospholipids and sulfatide but not cholesterol or galactosylceramide [24].
• The PLP gene in one of two affected males and the carrier mother of this family exhibited a single base difference in the more than 2 kb of the PLP gene sequenced, a C----T transition that would create a serine substitution for proline at the carboxy end of the protein [25].
• A single T----C transition results in the substitution of a charged amino acid residue, arginine, for tryptophan in one of the four extremely hydrophobic domains of the PLP protein [26].

Physical interactions of PLP1

• Purification and characterization of the mammaglobin/lipophilin B complex, a promising diagnostic marker for breast cancer [27].

Regulatory relationships of PLP1

• Thus, one means whereby zinc stabilises association of MBP with brain myelin membranes may be by promoting its binding to PLP [28].
• We also found that glucocorticoids stimulate the translation of MBP and PLP mRNAs and inhibit the translation of CNP mRNA in cell-free systems [29].
• Collectively, these results indicate that myelin proteolipid protein peptide-specific CD8+ CTL may be an important source of proinflammatory soluble mediators that could promote and mediate the inflammatory response in MS demyelination [30].

Other interactions of PLP1

• An immunohistochemical study, which can detect the specific expression of PLP, myelin basic protein, myelin-associated glycoprotein, and platelet-derived growth factor receptor alpha subunit in brain tissues, showed that the myelination was almost the same as that of age-matched controls [31].
• PLP and MAG were detected rostrally between 12 to 14 GW [32].
• The replicase polyprotein of murine coronavirus is extensively processed by three proteinases, two papain-like proteinases (PLPs), termed PLP1 and PLP2, and a picornavirus 3C-like proteinase (3CLpro) [33].
• The differential expression seen by microarray for CART as well as MBP, MOBP, and PLP was verified by RT-PCR [34].
• We found that there was higher frequency of increased T-cell reactivity to immunodominant PLP peptides in women than in men, particularly in non-MS individuals [35].

Analytical, diagnostic and therapeutic context of PLP1

• Studies of various PLP1 mutants in humans and animal models have shed light on the genomic, molecular, and cellular pathogeneses of PMD/SPG2 [36].
• Northern blot analysis revealed a 3.2-kilobase (kb) PLP mRNA that was present at higher abundance in the 21-23-week spinal cord RNA than in the 17-19-week or the 11-14-week samples [37].
• Several clones with proper cytoplasmic MBP or surface PLP localization were obtained and characterized by flow cytometry and indirect immunostaining [38].
• A prenatal diagnosis on a chorionic villus sample (CVS) was carried out using single-strand conformation polymorphism (SSCP) analysis of a variant in exon 4 of the PLP gene [39].
• PLP gene duplications were detected by quantitative polymerase chain reaction and/or Southern blot analysis [40].

References