How to promote remyelination in MS

ECTRIMS 2020

How to promote remyelination in MS

2846 1601 Anne Carter, MA (Cantab)

Strategies to promote remyelination was a hot topic at this year’s virtual ACTRIMS/ECTRIMS joint meeting, with three expert presenters each addressing a different aspect of the subject, including the role of astrocytes, mechanisms of remyelination and amino acid transport in the central nervous system (CNS).

“The role of astrocytes in remyelination is controversial”

Veronique Miron (University of Edinburgh, Edinburgh, UK) opened the Hot Topic session with an overview of the dual function of astrocytes in remyelination, regulated by the Nrf2 protein. While astrocytes have been shown to support remyelination via several processes, they have also been shown to impede these steps. Dr Miron and her team therefore worked to uncover the molecular mechanisms underpinning these interactions, with the ultimate aim to understand how to target astrocytes to support remyelination in multiple sclerosis (MS).

Through a series of in vivo experiments, Dr Miron’s group identified that the translatome of astrocytes changes during efficient remyelination. More specifically, the Nrf2 pathway was found to be transiently activated in astrocytes early during remyelination, then the cholesterol biosynthesis pathway becomes enriched at the onset of oligodendrocyte differentiation. Following further investigation, it appears that efficient remyelination requires the Nrf2 pathway to be downregulated in order for cholesterol biosynthesis to increase. It is known that “different lesion types have different remyelination potential”, and the inverse relationship between Nrf2 and cholesterol biosynthesis may be part of this.

“Inflammation plays an important role in remyelination”

Continuing on the theme of different remyelination potential of MS lesions, Mikael Simons (Technical University of Munich/ Deutsches Zentrum für Neurodegenerative Erkrankungen Munich, Munich, Germany) discussed mechanisms of remyelination. He explained that active lesions in MS have three potential “fates”: becoming a chronic scar, existing as a chronic active lesion, or remyelination. As Dr Simons shared, “One important question that we are interested in is to understand how a lesion can take these different fates.” It seems that age is an important factor for recovery, with younger patients (aged <40 years) tending to have lesions with better recovery than older patients.1 In a mouse model, Dr Simons and his team found that older animals had more inflammatory cells in lesions than younger animals. For remyelination to occur, the initial inflammatory response must be resolved to allow oligodendrocytes to differentiate, and it seems this process is deficient in aged animals. With this knowledge, there might be a “window of opportunity” to treat active lesions to target inflammation and enhance remyelination. Remyelination strategies in chronic lesions that no longer have inflammation may be more of a challenge.

“The CNS microenvironment may not be favourable for remyelination”

Jeffrey Huang (Georgetown University, Washington D.C., USA) ended the hot topic session with a discussion of his team’s work on amino acid transportation in remyelination. Building on the topic of inflammation in remyelination, Dr Huang shared how high levels of amino acids in inflammatory lesions led his team to investigate whether the amino acid transporter Slc7a5 could be involved in macrophage/microglia activation. When Slc7a5 was inhibited, lesions in mice showed a significantly reduced pro-inflammatory activation of macrophages and microglia, although the relative density of the cells was unaffected. This suggests that Slc7a5 inhibition does not deplete or kill macrophages or microglia in lesions, but rather reduces their activation.

For more coverage from ECTRIMS 2020, please click here.


References

1. Absinta M, et al. J Clin Invest. 2016;126:2597–609.

Brainwork is supported by unrestricted grants from: