Disease relevance of Plp1

• The X chromosome-linked PLP/DM-20 gene is the CNS myelin gene most frequently associated with mutations, resulting in dysmyelination in several species including man (Pelizaeus-Merzbacher disease, X-linked Spastic Paraplegia) [1].
• We have undertaken to measure the level of GFAP-mRNA as an index of gliosis in the brain of jimpy (jp) and shiverer (shi) murine mutants, in which hypomyelination is either severe or moderate, respectively [2].
• Increased dosage of the proteolipid protein (Plp) gene causes CNS disease (Pelizaeus-Merzbacher disease [PMD]), which has many similarities to disorders of the PNS associated with duplication of the peripheral myelin protein-22 (PMP22) gene locus [3].
• Experimental autoimmune encephalomyelitis (EAE) induced with myelin proteolipid protein (PLP) residues 139-151 (HSLGKWLGHPDKF) can be prevented by treatment with a T cell receptor (TCR) antagonist peptide (L144/R147) generated by substituting at the two principal TCR contact residues in the encephalitogenic peptide [4].
• Myelin basic protein (MBP) and proteolipid protein (PLP), the most abundant proteins of central nervous system (CNS) myelin, have been extensively studied as possible primary target antigens in multiple sclerosis (MS), a primary demyelinating autoimmune disease of the CNS [5].

Psychiatry related information on Plp1

• Jimpy mice spent less time engaged in coordinated motor activities (locomotion and grooming) than normal littermates, and more time engaged in slight movement or remaining inactive [6].

High impact information on Plp1

• Recently we have found that unmanipulated SJL mice that are highly susceptible to EAE also maintain a very high frequency of T cells responding to an encephalitogenic epitope of a myelin antigen proteolipid protein (PLP) 139-151 in the peripheral repertoire [7].
• Based on the PLP 139-151 system, we propose a model in which activation with foreign antigens can result in the generation of pathogenic memory T cells that mediate autoimmunity [7].
• This is not due to lack of expression of myelin antigens in the thymus resulting in escape of PLP 139-151 reactive cells from central tolerance, but is due to expression of a splice variant of PLP named DM20, which lacks the residues 116-150 [7].
• On the other hand, connatal PMD mutations lead to the accumulation of both mutant PLP and DM20 proteins in the ER of COS-7 cells with little of either isoform transported to the cell surface [8].
• We report a cellular basis for the distinction between two disease subtypes, classical and connatal, based on protein trafficking of the two PLP gene products (PLP and DM20) [8].

Chemical compound and disease context of Plp1

• In experimental autoimmune encephalomyelitis (EAE) induced with myelin proteolipid protein (PLP) peptide 139-151, we have previously shown that the disease is mediated by Th1 cells, which recognize tryptophan 144 as the primary TCR contact point [9].
• Copolymer 1 inhibits chronic relapsing experimental allergic encephalomyelitis induced by proteolipid protein (PLP) peptides in mice and interferes with PLP-specific T cell responses [10].
• When stressed by CO2 to produce a respiratory acidosis or by injection of distilled water to produce brain edema, the Jimpy mouse brain has water and ionic responses essentially like those in controls [11].

Biological context of Plp1

• Finally, we have localized the murine IL-2R gamma gene, Il2rg, to the X chromosome between Rsvp and Plp and demonstrated that a defect in IL-2R gamma is not responsible for the X chromosome-linked xid mutation, which maps to this same region [12].
• This suggests that the lethal phenotype associated with the majority of PLP gene mutations is a complex combination of loss and gain-of-function effects of a mutant myelin protein [1].
• Here, we demonstrate that these PLP-minus mice show no pleiotropism as mice carrying point mutations within the PLP gene [13].
• The core and particular importance of these four residues in PLP 56-70 was confirmed in vitro using amino acid substitution studies [14].
• These results indicate that the jp, jpmsd, and qk mutations exhibit qualitatively similar phenotypic effects on MBP gene expression but the magnitude of the effect is proportional to the extent of hypomyelination in each mutant [15].

Anatomical context of Plp1

• Its expression increases in parallel with that of major myelin genes Mbp and Plp1 [16].
• We propose that adhesion properties of the extracellular domains of PLP are responsible for the tight apposition of the plasma membrane processes of oligodendrocytes wrapping axons to form the compact myelin sheath [13].
• In fact, upon transgenic overexpression PLP becomes a prominent peripheral myelin protein, whereas in normal Schwann cells PLP is restricted from entering the myelin compartment [1].
• The pathology of most PLP gene mutations is characterized by hypomyelination, glial cell proliferation, increased numbers of microglia, and premature oligodendrocyte death [1].
• Jimpy (jp), myelin synthesis-deficient (jpmsd), and quaking (qk) are mutations which affect myelination to different degrees in the mouse central nervous system (CNS) [15].

Associations of Plp1 with chemical compounds

• We have confirmed an earlier report of a point mutation in exon 6 of the jimpymsd PLP gene, which converts an alanine to a valine.(ABSTRACT TRUNCATED AT 250 WORDS)[17]
• The shaking pup (shp) is a canine mutation that affects the myelin protein proteolipid protein (PLP) and its smaller and less abundant isoform, DM20, with proline replacing histidine(36), resulting in a severe myelin deficiency in the central nervous system [18].
• Amino acid analyses of MBPs from jimpy brain showed an increase in glutamic acid, alanine and ornithine, and a decrease in histidine, arginine and proline [19].
• MBPs isolated from dysmyelinating mutant mouse brains, such as jimpy (jp/y) and quaking (qk/qk), contained a much higher level of Me2(asym)Arg relative to the other two methyl derivatives and also in comparison with those levels in the mother brain MBP [20].
• By comparison, the proportion of jimpy oligodendrocytes expressing surface myelin/oligodendrocyte glycoprotein is reduced by approximately 34% [21].

Physical interactions of Plp1

• However, under the isotonic condition, PLP binds inositol hexakisphosphate (InsP6) significantly, not inositol 1,3,4,5-tetrakisphosphate [22].
• This finding rules out the possibility that contaminating F0 ATPase gives rise to the DCCD binding exhibited by PLP and confirms the possibility that PLP has proton channel activity, as suggested by Lin and Lees (1,2) [23].

Regulatory relationships of Plp1

• MBP mRNA levels remained well below control levels in jp/Y brain polyribosomes throughout early postnatal development [24].
• We have found that steroids, such as glucocorticoids, stimulate the translation of MBP and PLP mRNAs in cell-free systems and inhibit the translation of CNP mRNA [25].
• Normal and jimpy oligodendrocytes in secondary cultures were transfected with plasmids containing the SV40 T-antigen gene expressed under the control of the mouse metallothionein-I promoter [26].
• In contrast, no significant difference in GS mRNA content was detected between control and jimpy brain tissue [27].
• We used compound heterozygote mice to study the long-term fate of oligodendrocytes expressing either the jimpy or rumpshaker allele against a background of cells expressing a Plp-null allele [28].

Other interactions of Plp1

• At monthly intervals after immunization with p139-151, responses to PLP 249-273, MBP 87-99, and PLP 137-198 were sequentially accumulated in al mice examined [29].
• Further meiotic mapping in the mouse placed Smcx in the Plp-Pdha1 interval [30].
• The fine specificity of these epitopes was further investigated using frame-shifted peptides, which indicated cores between MOG 9-15 (GYPIRAL) and PLP 62-68 (NVIHAFQ) [14].
• OSP/claudin-11 and PLP are both tetraspan proteins concentrated in CNS myelin [31].
• Immunoblotting analysis did not reveal an increased apparent Mr for MAG in the Jimpy mouse, as has been observed in some other hypomyelinating murine mutants [32].

Analytical, diagnostic and therapeutic context of Plp1

• PLP was reduced more than the other proteins, as it was not detected by an immunoblotting technique that was capable of detecting 0.5% of the control level [32].
• Northern blots showed the presence of multiple mouse PLP RNAs, the developmental expression of which coincided with myelination [33].
• However, MBP and PLP polypeptides could not be detected by western blot or immunocytochemical staining at either the permissive or nonpermissive temperature [34].
• Immunoelectron microscopy using gold particles showed that the truncated endogenous jimpy PLP was distributed throughout the cytoplasm and in association with the plasma membrane of cell bodies and processes [26].
• The reverse transplantations (newborn shi or normal into newborn jp brain) demonstrate that the jp environment does not modify the phenotype of normal or shi ODCs [35].

References