Karim, Saadia Ansari
The effects of increased Plp1 gene dosage on expression and processing of myelin proteins.
PhD thesis, University of Glasgow.
Full text available as:
Mutations in proteolipid protein 1 (PLP1), an X-linked gene causes Pelizaeus-Merzbacher disease (PMD) in humans. The most frequent cause of PMD is the duplication of PLP1, which encodes the major myelin membrane protein of the human CNS. The #66 transgenic mice with extra copies of the wild type Plp1 gene are a valid model of PMD caused by increased gene dosage (Readhead et al., 1994). These mice develop dysmyelinating or demyelinating phenotypes dependant on the gene dosage. This study investigated the effects of both low and high increased Plp1 gene dosage on various different selected aspects of myelin, including morphology, message and protein levels of PLP/DM20 and other representative myelin proteins and PLP/DM20 dynamics.
Early in development mice with low increased gene dosage (hemizygous) are indistinguishable at the protein and myelin levels from their wild type littermates. During myelination these animals display elevated levels of PLP/DM20 in the oligodendrocyte cell body and alterations in other myelin protein levels and to the structure of myelin but these are transitory effects. These transient changes suggest the oligodendrocytes at low gene dosage retain the ability to regulate expression, production and incorporation of proteins into myelin thus maintaining the normal process of myelination.
At high increased gene dosage (homozygous), oligodendrocytes in culture, pre and early myelinating oligodendrocytes in vivo and oligodendrocytes in vivo during peak myelination all exhibit elevated levels of PLP/DM20 in the their cell bodies. The protein is sequestered into autophagic vacuoles and late endosomes/lysosomes (LE/Ls), while the levels in myelin are reduced compared to wild type and hemizygous cells. Synthesis, partitioning with lipids and incorporation of PLP/DM20 are all also affected in the homozygous animals. The increased Plp1 gene dosage does affect other myelin proteins, in particular MBP, which showed a consistent and dramatic reduction in oligodendrocytes and myelin.
These results indicate the heterogeneity of phenotypes and underlying changes caused by low and high increased Plp1 gene dosage. The cause of the dysmyelination observed in #66 mice and patients with PMD does not appear to be due to one single change in myelinogenesis. Each alteration observed in #66 transgenic mice could be a contributing factor. Importantly, the perturbation of MBP expression, in the light of this gene’s pivotal role in myelination, highlights that the relationship between Plp1 and Mbp expression is implicated in the pathogenesis of dysmyelination.
Actions (login required)