Mechanism of Demyelination

Leitner DF, Todorich B, Zhang X, Connor JR. Semaphorin4A Is Cytotoxic to Oligodendrocytes and Is Elevated in Microglia and Multiple Sclerosis. ASN Neuro. 2015 May 29;7(3). pii: 1759091415587502. doi: 10.1177/1759091415587502. Print 2015 May

We have previously established that T cell immunoglobulin and mucin domain containing 2 (Tim2) is an H-ferritin receptor on oligodendrocytes (OLs). Tim2 also binds Semaphorin4A (Sema4A). Sema4A is expressed by lymphocytes, and its role in immune activation is known; however, its relationship to diseases that are known to have myelin damage has not been studied. In this study, we demonstrate that Sema4A is cytotoxic to OLs in culture: an effect accompanied by process collapse and membrane blebbing, We further demonstrate that Sema4A preferentially binds to primary OLs but not astrocytes: an observation consistent with the lack of expression of Tim2 on astrocytes. We found that Sema4A protein levels are increased within multiple sclerosis plaques compared with normal-appearing white matter and that Sema4A induces lactate dehydrogenase release (a marker of tissue damage) in a human OL cell line. The chief cellular source of Sema4A within the multiple sclerosis plaques appears to be infiltrating lymphocytes and microglia. Macrophages are known to express Sema4A, so we interrogated microglia as a potential source of Sema4A in the brain. We found that rat primary microglia express Sema4A which increased after activation. Because activated microglia accumulate iron, we determined whether iron status influenced Sema4A and found that iron chelation decreased Sema4A and iron loading increased Sema4A in activated microglia. Overall, our data implicate Sema4A in the destruction of OLs and reveal that its expression is sensitive to iron levels.

Semaphorins are a class of secreted and membrane proteins that act as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. They are usually cues to deflect axons from inappropriate regions, especially important in neural system development. The major class of proteins that act as their receptors are called plexins. The main receptors for semaphorins are plexins, which have established roles in regulating Rho-family GTPases. The Semaphorins are grouped into eight major classes based on structure and phylogenetic tree analyses.The first seven are ordered by number, from class 1 to class 7. The eighth group is class V, where V stands for virus. Classes 1 and 2 are found in invertebrates only, whilst classes 3, 4, 6, and 7 are found in vertebrates only. Class 5 is found in both vertebrates and invertebrates, and class V is specific to viruses. Classes 1 and 6 are considered to be homologues of each other; they are each membrane bound in invertebrates and vertebrates, respectively. Each class of Semaphorin has many subgroups of different molecules that share similar characteristics. For example, Class 4 Semaphorins range from Sema4a to Sema4g. SEMA4A is a member of the semaphorin family of soluble and transmembrane proteins. Semaphorins are involved in guidance of axonal migration during neuronal development and in immune responses. In this study they show that this is a toxic to the myelin forming oligodendrocytes