Oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), and astrocytes constitute macroglia. This review deals with the recent progress related to the origin and differentiation of the oligodendrocytes, their relationships to other neural cells, and functional neuroglial interactions under physiological conditions and in demyelinating diseases. One of the problems in studies of the CNS is to find components, i.e., markers, for the identification of the different cells, in intact tissues or cultures. In recent years, specific biochemical, immunological, and molecular markers have been identified. Many components specific to differentiating oligodendrocytes and to myelin are now available to aid their study. Transgenic mice and spontaneous mutants have led to a better understanding of the targets of specific dys- or demyelinating diseases. The best examples are the studies concerning the effects of the mutations affecting the most abundant protein in the central nervous myelin, the p...

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Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and α-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.

Function and genetics of dystrophin and dystrophin-related proteins in muscle

A fundamental function of epithelia and endothelia is to separate different compartments within the organism and to regulate the exchange of substances between them. The tight junction (TJ) constitutes the barrier both to the passage of ions and molecules through the paracellular pathway and to the movement of proteins and lipids between the apical and the basolateral domains of the plasma membrane. In recent years more than 40 different proteins have been discovered to be located at the TJs of epithelia, endothelia and myelinated cells. This unprecedented expansion of information has changed our view of TJs from merely a paracellular barrier to a complex structure involved in signaling cascades that control cell growth and differentiation. Both cortical and transmembrane proteins integrate TJs. Among the former are scaffolding proteins containing PDZ domains, tumor suppressors, transcription factors and proteins involved in vesicle transport. To date two components of the TJ filaments have been identified: occludin and claudin. The latter is a protein family with more than 20 members. Both occludin and claudins are integral proteins capable of interacting adhesively with complementary molecules on adjacent cells and of co-polymerizing laterally. These advancements in the knowledge of the molecular structure of TJ support previous physiological models that exhibited TJ as dynamic structures that present distinct permeability and morphological characteristics in different tissues and in response to changing natural, pathological or experimental conditions.

Tight junction proteins.

S-Adenosylmethionine (AdoMet or SAM) plays a pivotal role as a methyl donor in a myriad of biological and biochemical events. Although it has been claimed that AdoMet itself has therapeutic benefits, it remains to be established whether it can be taken up intact by cells. S-Adenosylhomocysteine (AdoHcy), formed after donation of the methyl group of AdoMet to a methyl acceptor, is then hydrolyzed to adenosine and homocysteine by AdoHcy hydrolase. This enzyme has long been a target for inhibition as its blockade can affect methylation of phospholipids, proteins, DNA, RNA, and other small molecules. Protein carboxymethylation may be involved in repair functions of aging proteins, and heat shock proteins are methylated in response to stress. Bacterial chemotaxis involves carboxymethylation and demethylation in receptor-transducer proteins, although a similar role in mammalian cells is unclear. The precise role of phospholipid methylation remains open. DNA methylation is related to mammalian gene activities, s...

S-Adenosylmethionine and methylation.

Glial cells produce myelin and contribute to axonal morphology in the nervous system. Two myelin membrane proteolipids, PLP and DM20, were shown to be essential for the integrity of myelinated axons. In the absence of PLP-DM20, mice assembled compact myelin sheaths but subsequently developed widespread axonal swellings and degeneration, associated predominantly with small-caliber nerve fibers. Similar swellings were absent in dysmyelinated shiverer mice, which lack myelin basic protein (MBP), but recurred in MBP*PLP double mutants. Thus, fiber degeneration, which was probably secondary to impaired axonal transport, could indicate that myelinated axons require local oligodendroglial support.

https://science.sciencemag.org/content/sci/280/5369/1610.full.pdf

Axonal swellings and degeneration in mice lacking the major proteolipid of myelin

Protein zero of peripheral nerve myelin: Biosynthesis, membrane insertion, and evidence for homotypic interaction

PROTEOLIPID protein (PLP; Mr 30,000) is a highly conserved major polytopic membrane protein in myelin but its cellular function remains obscure. Neurological mutant mice can often provide model systems for human genetic disorders. Mutations of the X-chromosome-linked PLP gene are lethal, identified first in the jimpy mouse1,2 and subsequently in patients with PelizaeusMerzbacher disease3,4. The unexplained phenotype of these mutations includes degeneration and premature cell death of oligodendrocytes with associated hypomyelination5. Here we show that a new mouse mutant rumpshaker6 is defined by the amino-acid substitution Ile-to-Thr at residue 186 in a membrane-embedded domain of PLP. Surprisingly, rumpshaker mice, although myelindeficient, have normal longevity and a full complement of morphologically normal oligodendrocytes7. Hypomyelination can thus be genetically separated from the PLP-dependent oligodendrocyte degeneration. We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum8 of Pelizaeus–Merzbacher disease.

Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene

Periaxin, a novel protein of myelinating schwann cells with a possible role in axonal ensheathment

https://www.cell.com/trends/neurosciences/pdf/0166-2236(93)90196-S.pdf

The distribution of myelin basic protein mRNAs within myelinating oligodendrocytes

The interaction of spin-labeled lipids with the myelin proteolipid apoprotein in complexes with dimyristoylphosphatidylcholine of varying lipid/protein ratios has been studied with electron spin resonance spectroscopy. A first shell of approximately 10 lipids per 25 000-dalton protein is found to be motionally restricted by the protein interface. This stoichiometry is consistent with a hexameric arrangement of the protein in the membrane. A selectivity of the various spin-labeled lipids for the motionally restricted component at the protein interface is found in the order stearic acid greater than phosphatidic acid greater than cardiolipin approximately greater than phosphatidylserine greater than phosphatidylglycerol approximately equal to phosphatidylcholine greater than phosphatidylethanolamine greater than androstanol approximately greater than cholestane.

Peter J. Brophy

Papers

Protein zero of peripheral nerve myelin: Biosynthesis, membrane insertion, and evidence for homotypic interaction

Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene

Periaxin, a novel protein of myelinating schwann cells with a possible role in axonal ensheathment

The distribution of myelin basic protein mRNAs within myelinating oligodendrocytes

Stoichiometry and specificity of lipid-protein interaction with myelin proteolipid protein studied by spin-label electron spin resonance.