Discovery of Pathways that Promote Remyelination

Posted by Ellen Burns on April 26th, 2022

In the evolutionary history of vertebrates, the emergence of myelin has made the transmission of neural signals much faster, and if humans evolve like invertebrate squid, the vertebral diameter of humans may be thicker than that of giant red fir trees. Insulating myelin sheaths encapsulate nerve axons, thereby allowing rapid conduction of action potentials between neurons, and in addition, myelin sheaths can also provide metabolic support, physical protection, and trophic factors for neuronal axons, thereby preventing axonal degeneration. In the central nervous system, myelin is generated by oligodendrocytes, which are differentiated from oligodendrocyte precursor cells (OPC). In some demyelinating diseases, such as multiple sclerosis and white matter lesions, there are many OPCs in the lesion, but they cannot differentiate into mature oligodendrocytes, and our understanding of OPC differentiation to myelinate is still not deep enough, therefore, in-depth exploration of the factors of OPC differentiation is very important for the treatment of these diseases.

The surface area of oligodendrocytes becomes thousands of times larger during differentiation and needs to undergo very active cargo transport. COPII mediates the transport of membrane proteins and soluble proteins from the endoplasmic reticulum to the Golgi apparatus, and abnormal function of COPII inhibits protein secretion and has effects on cell differentiation and homeostasis, and many studies have shown a link between COPII components and human diseases, such as Sec31 mutations leading to severe neurological syndromes. However, the physiological functions and underlying mechanisms of COPII components in oligodendrocyte differentiation and myelination are currently unknown.

Recently, for the first time, researchers have discovered that COPII-mediated autocrine plays an important function in oligodendrocyte differentiation and remyelination, providing new ideas for the treatment of demyelination-related diseases.

In this study, the authors first confirmed that COPII-mediated membrane vesicle transport facilitates myelination using membrane vesicle transport drugs, and inhibition of COPII membrane vesicle transport leads to reduced remyelination ability. The authors then constructed conditional knockout mice for the COPII protein Sec13, which is required for OPC differentiation to form myelin, as confirmed in vivo, in the environment, and in the process of myelin damage repair in mice.

Mechanistically, the authors demonstrated that Sec13 could participate in the process of myelination through autocrine secretion of PTN. The authors found that conditioned medium from differentiated oligodendrocytes could promote OPC differentiation, and using liquid chromatography mass spectrometry, increased secreted proteins were detected during OPC differentiation, and loss of Sec13 resulted in decreased secretion of these proteins. Among the secreted proteins regulated by Sec13, PTN can significantly promote the differentiation of OPC after being secreted, while PTN with mutated signal peptide cannot be secreted to play a promoting role, and the secretion of PTN depends on Sec13. In addition, PTN can replenish the phenotype of abnormal OPC differentiation brought about by Sec13 knockdown, illustrating that Sec13 regulation of myelination is mainly achieved through the secretion of PTN. Through co-immunoprecipitation and western blot experiments, it was found that PTN acts on the cell membrane receptor PTPRZ1, causing phosphorylation of P190, which promotes myelination.

Finally, in a model of lysophosphatide-induced myelin injury, the authors found that PTN expression was upregulated after myelin injury. Viral knockdown of PTN expression inhibits remyelination progression; in contrast, overexpression of PTN, can promote the rate of remyelination. The study addresses the physiological function of COPII-mediated membrane vesicle trafficking during myelination by primary cells and mouse models, pointing to the PTN-PTPRZ1 pathway as a possible therapeutic target for demyelinating diseases.