The proteolipid protein gene and myelin disorders in man and animal models

Abstract

The two proteins, proteolipid protein and DM20, which are encoded by alternative transcripts from the proteolipid protein ( PLP ) gene, are major components of central nervous system myelin. In man, mutations of these proteins cause Pelizaeus-Merzbacher disease (PMD), an X-linked dysmyelinating neuropathy. The mutations found are very varied, ranging from deletions, loss-of-function and missense mutations to additional copies of the gene. This same range of known genetic defects has been observed in animal models with spontaneous and engineered Plp gene mutations. The relationship between genotype and phenotype is remarkably close in the animal models and the PMD cases, making them useful models for studying the mechanisms of PLP gene-related disease. As a result, it has become clear that the PLP gene plays a wider role in neural development in addition to its function as a structural component of myelin. It has also emerged that duplications of the PLP gene are the commonest mutation in PMD. Genetic disorders arising from a dosage effect may be more common than previously recognized. The study of the PLP gene in this rare disorder is, therefore, contributing both to our understanding of neural development and maintenance and to the mechanisms of human genetic disorders.

Functional Genomic and Proteomic Analysis Reveals Disruption of Myelin-Related Genes and Translation in a Mouse Model of Early Life Neglect

“…MBP is also a myelin component and mutations in Mbp are responsible for the shiverer mouse phenotype which involves deficient CNS myelination as well as tremors and convulsions, a phenotype that is reversed by introduction of a functional Mbp gene (Readhead et al, 1987). Plp1 is genetically associated with Pelizaeus–Merzbacher disease, a hypomyelinative leukodystrophy (Yool et al, 2000), and deletion of Plp1 from the mouse leads to axonal disruption suggesting that olidodendrocytes are required for axon function (Edgar et al, 2004b). Mice deficient in Ugt8a show hypomyelination as well as increased numbers of oligodendrocytes (Marcus et al, 2000).…”

Mitochondrial protein translocases for survival and wellbeing

“…Patients who suffer from Pelizaeus-Merzbacher disease (PMD), in addition to rodent models of PMD, carry mutations in the PLP gene. This gene encodes the proteolipid protein (PLP) and its shorter isoform DM20, the two most abundant membrane proteins in myelin [106]. The consequences of disease-related PLP gene duplication, which are phenotypically more severe than null mutations, include the accumulation of PLP in mitochondria.…”

Where, when and how much: regulation of myelin proteolipid protein gene expression

“…Other transgenic studies have demonstrated that overexpression of the Plp gene leads to glial cell degeneration and hypomyelination [133,134] or late-onset neurodegeneration [135]. This sensitivity to moderate overexpression of the Plp gene may help to explain why humans who have Plp gene duplications develop PMD [reviewed in 136].…”