Making myelin basic protein -from mRNA transport to localized translation

Abstract

In the central nervous system (CNS) of most vertebrates, oligodendrocytes enwrap neuronal axons with extensions of their plasma membrane to form the myelin sheath. Several proteins are characteristically found in myelin of which myelin basic protein (MBP) is the second most abundant one after proteolipid protein. The lack of functional MBP in rodents results in a severe hypomyelinated phenotype in the CNS demonstrating its importance for myelin synthesis. Mbp mRNA is transported from the nucleus to the plasma membrane and is translated locally at the axon–glial contact site. Axonal properties such as diameter or electrical activity influence the degree of myelination. As oligodendrocytes can myelinate many axonal segments with varying properties, localized MBP translation represents an important part of a rapid and axon-tailored synthesis machinery. MBP’s ability to compact cellular membranes may be problematic for the integrity of intracellular membranous organelles and can also explain why MBP is transported in oligodendrocytes in the form of an mRNA rather than as a protein. Here we review the recent findings regarding intracellular transport and signaling mechanisms leading to localized translation of Mbp mRNA in oligodendrocytes. More detailed insights into the MBP synthesis pathway are important for a better understanding of the myelination process and may foster the development of remyelination therapies for demyelinating diseases.

Membrane Association Landscape of Myelin Basic Protein Portrays Formation of the Myelin Major Dense Line

“…During CNS myelination, MBP is translated in the vicinity of the growing membrane from transported mRNA 52 . The local synthesis of MBP is likely to be a key triggering factor for myelin membrane compaction.…”

Regionally-specific alterations in myelin proteins in nonhuman primate white matter following prolonged cocaine self-administration

“…These studies focused primarily on transcripts in striatal and prefrontal cortical tissue, however, and although in one report PLP mRNA was altered in the internal capsule (Kristiansen et al, 2009), measurements were not made in samples of callosal or other subcortical white matter, and this difference in the anatomical targets between these two studies and the present investigation may underlie the discrepant findings. In the case of MBP, for example, protein synthesis occurs at the oligodendritic/neuronal contact site, where multiple signaling mechanisms regulate translation, posttranslational modifications, and incorporation into the myelin sheath (Muller et al, 2013). Here, biosynthesis, modification, and trafficking are tightly regulated to respond in a regionally-specific manner to local axonal requirements.…”

The Major Myelin-Resident Protein PLP Is Transported to Myelin Membranes via a Transcytotic Mechanism: Involvement of Sulfatide

“…Thus, following its biosynthesis at the rough endoplasmic reticulum and processing through the Golgi apparatus (9,10), the transmembrane protein PLP is transported via vesicles to the myelin membrane (11,12). In marked contrast, MBP, a peripheral membrane protein facing the cytoplasm, is synthesized at and associates with the myelin membrane on site, involving myelin membrane-directed transport of its mRNA rather than the native protein (13,14). In addition, to limit ectopic assembly and premature compaction of myelin membranes, the protein-mediated biogenesis of myelin membranes is tightly regulated in both time and space (reviewed in reference 6).…”