Cellular and molecular aspects of myelin protein gene expression

Abstract

The cellular and molecular aspects of myelin protein metabolism have recently been among the most intensively studied in neurobiology. Myelination is a developmentally regulated process involving the coordination of expression of genes encoding both myelin proteins and the enzymes involved in myelin lipid metabolism. In the central nervous system, the oligodendrocyte plasma membrane elaborates prodigious amounts of myelin over a relatively short developmental period. During development, myelin undergoes characteristic biochemical changes, presumably correlated with the morphological changes during its maturation from loosely-whorled bilayers to the thick multilamellar structure typical of the adult membrane. Genes encoding four myelin proteins have been isolated, and each of these specifies families of polypeptide isoforms synthesized from mRNAs derived through alternative splicing of the primary gene transcripts. In most cases, the production of the alternatively spliced transcripts is developmentally regulated, leading to the observed protein compositional changes in myelin. The chromosomal localizations of several of the myelin protein genes have been mapped in mice and humans, and abnormalities in two separate genes appear to be the genetic defects in the murine dysmyelinating mutants, shiverer and jimpy. Insertion of a normal myelin basic protein gene into the shiverer genome appears to correct many of the clinical and cell biological abnormalities associated with the defect. Most of the dysmyelinating mutants, including those in which the genetic defect is established, appear to exhibit pleiotropy with respect to the expression of other myelin genes. Post-translational events also appear to be important in myelin assembly and metabolism. The major myelin proteins are synthesized at different subcellular locations and follow different routes of assembly into the membrane. Prevention of certain post-translational modifications of some myelin proteins can result in the disruption of myelin structure, reminiscent of naturally occurring myelin disorders. Studies on the expression of myelin genes in tissue culture have shown the importance of epigenetic factors (e.g., hormones, growth factors, and cell-cell interactions) in modulating myelin protein gene expression. Thus, myelinogenesis has proven to be very useful system in which to examine cellular and molecular mechanisms regulating the activity of a nervous system-specific process.

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

“…Furthermore, if the mutated PMP22 is shunted directly to endosomes / lysosomes without being incorporated into myelin, it would have to be associated with other myelin proteins, perhaps as "premyelin" vesicles, to account for the increased accumulation with P0 and MBP in endosomes / lysosomes after chloroquine treatment. The possibility of an effect on "premyelin" vesicles seems particularly unlikely for MBP, a cytoplasmic protein synthesized on free polyribosomes in close proximity to myelin assembly (for review, see Campagnoni and Macklin, 1988). Ultimately though, this putative pathway fails to explain why the leftover wild-type PMP22 and the other compact myelin proteins cannot support the formation of normal myelin over a longer period of time.…”

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

“…The developmental and tissue-specific expression of PLP is coordinately controlled with the other myelin proteins in the CNS (reviewed in refs. [2][3][4][5]. In the peripheral nervous system, PLP is the only myelin protein synthesized by nonmyelinating Schwann cells, glial cells that enwrap but do not myelinate axons.…”

Neonatal hypothyroidism affects the timely expression of myelin-associated glycoprotein in the rat brain.

“…Although an effect on mRNA transport from the nucleus to the cytoplasm cannot be discarded at present, it is likely that thyroid hormone is required to stabilize newly transcribed MAG mRNA during the earlier phases of myelination to allow for a rapid accumulation of the transcripts and protein production. This is not surprising, in view of the fact that although the main control on myelin gene expression is exerted at the level of transcription by oligodendrocyte-specific transcription factors (21)(22)(23)(24), there is also control at the posttranscriptional level. For example, glucocorticoids posttranscriptionally regulate the expression of basic protein and proteolipid protein (5 1 ).…”

“…Myelin is a multilamelar membrane structure surrounding many axons in the central and peripheral nervous system (21)(22)(23)(24). Central myelin is produced by differentiated oligodendrocytes and consists mainly of lipids (75%) and proteins (25%).…”