Myelin and re-myelination in Multiple Sclerosis and Canavan Disease

Abstract

Myelin sheath formation around axons is fundamentally important for central nervous system (CNS) function. Understanding the process of myelination, and the mechanism of immune-induced demyelination is essential in designing new therapeutic strategies for demyelinating autoimmune diseases like Multiple Sclerosis (MS), and dysmyelinating genetic diseases like Canavan Disease (CD).

Multiple Sclerosis is an autoimmune disease characterized by CNS inflammation, demyelination, and axonal degeneration. We used an MS mouse model, experimental autoimmune encephalomyelitis (EAE), to examine immune cell trafficking, and effects on demyelination in novel transgenic mice lacking astroglial CXCL10. We found that astroglial CXCL10 enhances spinal cord perivascular CD4+ lymphocyte accumulation and acute spinal cord demyelination, but does not play an important role in progressive axon loss in EAE.

We also investigated three aspects of glial cells and their involvement with myelin deficits and repair in EAE and CD. First, the origin of reactive astrocytes during EAE was controversial for many years. We were able to conclude that resident spinal cord astrocytes are restricted to their own lineages in EAE.

Second, oligodendroglial N-methyl-D-aspartate receptors (NMDARs) may contribute to the pathophysiology of MS and are being explored as targets for treatment. We investigated the contribution of oligodendroglial NMDARs in white matter injury during EAE. Our data suggest that oligodendroglial lineage NMDARs are not significant participants in the pathophysiology of EAE.

And third, we examined oligodendroglial development and CNS myelination in mice deficient in N-acetyltransferase 8 like (NAT8L) – the enzyme which synthesizes N-acetylaspartate (NAA) – to test the necessity of NAA for CNS myelin synthesis. Children with CD, a recessively inherited, neurodegenerative disease of infancy, lack expression of aspartoacylase (ASPA), an enzyme highly expressed in oligodendroglia, which cleaves NAA, resulting in markedly elevated CNS NAA levels in these children. In oligodendroglia, NAA is cleaved by ASPA to generate acetate, which can be used regenerate acetyl-CoA for myelin cholesterol and fatty acid synthesis. We found that CNS myelination proceeds normally in mice lacking NAT8L despite suppression of CNS NAA synthesis. This suggests that dysmyelination in Canavan Disease is not likely due to oligodendroglial acetate deficiency.