Galectins, (re)myelination and MS pathology

Galectins, (re)myelination and multiple sclerosis pathology

Identification of environmental signals that regulate oligodendrocyte (OLG) development and corresponding receptors on the cell surface through which these signals act, is necessary to understand both normal OLG development and their behaviour in demyelinating diseases, such as multiple sclerosis (MS). Recentfindings point to a role of lectins, i.e., glycan-binding proteins, in the interaction between cells ofthe CNS that are likely highly relevant to myelination and demyelination of axons. Indeed, prompted by recent reports in experimental MS animal models, it was of interest to define the expression profile of a special group of lectins -galectins- in control white matter (CWM) and MS lesions and analyze their roles on glia cell behaviour.
Our data revealed that among 11 different galectins tested, galectins-1, -3, -8 and -9 were present at detectable levels in CWM, and, interestingly, significantly enhanced in active MS lesions. On the cellular level, galectins localized to microglia/macrophages, astrocytes and endothelial cells. Intriguingly, galectin-9 displayed a distinctly different intracellular localization in microglia/macrophages when comparing active and inactive MS lesions, being restricted to the nuclei in active lesions, and primarily localizing in the cytoplasm in inactive lesions. Furthermore, enhanced levels of galectin-1were released by cultured astrocytes derived from MS patients.
Our data further revealed thatgalectin-4 expression is downregulated in developing postnatal rat brains, i.e., just before the onset of myelination. Neurons and OLGs, but not astrocytes and microglia, were identified as a source of galectin-4. Interestingly, cultured neurons but not OLGs released galectin-4, whereas receptor(s) for galectin-4 are transiently expressed on processes of pre-myelinating primary OLGs, but not on neurons. Intriguingly, when immature OLGs were treated with galectin-4, OLG differentiation was significantly delayed. In fact, upon galectin-4 treatment a subset of OLGs reverted to a morphologically less complex progenitor, with a concomitant increase of proliferation. Similarly, in myelinating dorsal root ganglion neuron (DRGN)-OLG co-cultures, decreased release of endogenous galectin-4 correlated with the onset of myelination, and exogenous addition of galectin-4 strongly inhibited myelination. Taken together, these findings indicate that neuronal galectin-4 expression/secretion likely determines the timing of myelination by preventing premature myelination. Hence, galectin-4 appears to be a novel soluble neuronal regulator of myelination.It is therefore tempting to suggest that a misbalance in galectin-4 timing and/or release, or the absence/masking of galectin-4 receptors in MS lesions might be responsible for remyelination failure in MS.Preliminary data show that galectin-4 is indeed re-expressed by virtually all axons in active MS lesions, whereas galectin-4 is only very occasionally expressed on axons in control white matter. In addition, in MS lesions galectin-4 immunoreactivity corresponds partly to activated microglia or infiltrated macrophages, the latter cells – based on our preliminary in vitro data - being more likely.
To conclude, the studies presented in this thesis have revealed novel and important insight into the role of galectins in interactions between glial cells and neurons throughout brain development, particularly during OLG differentiation and myelination, and in demyelinated MS lesions. The discovery of galactin-4, highlighted in this thesis as a new regulator of the timing of myelination, will add to an improved understanding of mechanisms of (re)myelination. Therefore, galectins are very promising targets for MS treatment since they are both potent regulators of inflammatory processes and glia cell behaviour.