How do different cell populations orchestrate myelin regeneration?

Abstract

Approximately 35 in 100,000 people are affected by diseases associated with loss of myelin, generally described as demyelinating diseases. Demyelinating diseases encompass many different pathological conditions characterized by heterogeneous and sometimes disease-specific etiopathological mechanisms. While several approaches aimed at ameliorating the symptoms and the progression of some of these diseases exist, the most effective cure for all demyelinating diseases would be regeneration of lost myelin. Myelin regeneration occurs spontaneously in the central nervous system in response to myelin damage but is inefficient for a variety of reasons, especially in human patients. In this review, we will discuss the contributions of different cell populations to the creation of conditions permissive for effective remyelination and to the formation of new myelin after injury. Moreover, we would like to highlight the importance of sphingolipids in the network of interactions between these cell populations. Mutations in genes encoding sphingolipid metabolic enzymes (such as GALC) represent a major risk factor for multiple sclerosis, and alterations in sphingolipid metabolism in specific cell types contribute to myelin damage. On the other hand, sphingolipid signaling, in particular through sphingosine 1 phosphate, directly affects the process of myelin regeneration, with distinct effects on different cellular populations.

Keywords: multiple sclerosis; rHIgM22; remyelination; sphingolipids; sphingosine 1-phosphate.

Figure 1:. Enzyme defects underlying metachromatic leukodystrophy and Krabbe disease.

In healthy OPCs/oligodendrocytes, ceramide in the Golgi is converted into galactosylceramide by ceramide galactosytransferase, and galactosylceramide in turn is the precursor for the synthesis of sulfatide by galactosylceramide sulfotransferase. In the catabolic pathway, sulfatide is cleaved to galactosylceramide by arylsulfatase, and galactosylceramide is subsequently hydrolyzed to ceramide by galactosylceramidase. Metachromatic leukodystrophy is due to deficiency of arylsulfatase A, resulting in the accumulation of undegraded sulfatide and of its deacylated derivative, lysosulfatide, formed by the action of lysosomal ceramidase, whereas Krabbe disease is caused by deficiency in galactosylceramidase with the consequent accumulation of galactosylceramide and of its deacylated metabolite galactosylsphingosine (psychosine). ASA, arylsulfatase; CDase, ceramidase; CGT, ceramide galactosyltransferase; CST, galactosylceramide sulfotransferase; GalC, galactosylceramidase.

Figure 2:. Metabolic pathways involved in the synthesis and degradation of the ‘sphingolipid rheostat’ mediators sphingosine 1 phosphate and ceramide.

The levels of sphingosine 1 phosphate and of ceramide in a given cell or tissue are the result of the activities of both biosynthetic and catabolic enzymes, and of a bidirectional flow of molecules between different subcellular locations. The generation of bioactive ceramide is mainly due to the hydrolysis of sphingomyelin by several sphingomyelinases, with different features and diverse subcellular locations, but catabolism of glycosphingolipids can also contribute to the pool of bioactive ceramide. In addition, dihydrosphingosine in the de novo biosynthetic pathway (not shown), as well as catabolic sphingosine, can be acylated by different ceramide synthases. Sphingosine 1 phosphate is mainly generated by the action of different sphingosine kinases in different cellular subcompartments. A major source of sphingosine for the synthesis of sphingosine 1 phosphate is ceramide cleavage by ceramidases. Hence, high levels of ceramide usually correspond to low levels of sphingosine 1 phosphate and vice versa (‘the sphingolipid rheostat’). In turn sphingosine 1 phosphate can be degraded by sphingosine 1 phosphate phosphatase or irreversibly cleaved by sphingosine 1-phosphate lyase. CDase, ceramidase; CerS, ceramide synthase; CGT, Ceramide galactosyltransferase; GalC, Galactosylceramidase; GBA, glucocerebrosidase; GCS, glucosylceramide synthase; SK, Sphingosine kinase; SMase, sphingomyelinase; SMS, sphingomyelin synthase; SPP, Sphingosine 1-phosphate phosphatase; SPGL1, Sphingosine 1-phosphate lyase.