Miron, Veronique

Chandran, Siddharthan

Molina-González, Irene

Medical Research Council (MRC)

2020-04-28T15:51:58Z

2020-04-28T15:51:58Z

2020-06-27

In Multiple Sclerosis (MS), the insulating membrane that ensheaths axons termed myelin, is lost by a process known as demyelination. Initial regeneration of myelin, termed remyelination, restores neuronal function. However, remyelination failure with disease leads to a loss of cognitive, sensory and motor functions. There are no currently approved therapies aimed at inducing remyelination, highlighting the need to investigate new targets that can promote this process. Astrocytes are the most abundant glial cell type in the central nervous system (CNS). They are known to support myelin formation in development and its maintenance during adulthood, yet their roles during remyelination are controversial and remain poorly understood. The work from this thesis explores the changes in astrocytes at the cellular and molecular level during remyelination. Using two different in vivo models of toxin induced demyelination, I have found that astrocytes during remyelination undergo a series of changes in numbers, reactivity (assessed by GFAP, vimentin, nestin and NFIA), and morphology, which indicate a temporal regulation of reactivity. Interestingly, I observed that astrocytes increase in reactivity at the time at which the myelin-forming cells, termed oligodendrocytes, differentiate to remyelinate axons. These findings suggest that astrocytes are important for regulating remyelination. To explore this, unbiased RNA-sequencing of astrocyte translating mRNA, isolated using translational ribosome affinity purification (TRAP), was used to identify changes in their gene expression. I found that astrocytes upregulate genes indicative of neuroprotective functions early after demyelination, characterised by the upregulation of the Nrf2 pathway. Subsequently, at the time of oligodendrocyte differentiation, astrocytes downregulate Nrf2 signalling and activate cholesterol biosynthesis, which is essential during myelination. Here, I hypothesised whether Nrf2 is an critical regulator of astrocyte functions that are important for remyelination. Hence, I used a transgenic mouse model in which Nrf2 is overexpressed in reactive astrocytes. The results suggested that upon sustained Nrf2 overexpression, cholesterol biosynthesis in astrocytes is impaired and consequently remyelination is poor. This study identifies a mechanism by which astrocytes regulate their functions after demyelination to control the timing of remyelination. These findings are of translation relevance, given that some MS therapies are thought to act via Nrf2 activation.

https://hdl.handle.net/1842/36997

http://dx.doi.org/10.7488/era/298

en

The University of Edinburgh

Rojo, R., et al. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. Nat Commun, 2019. 10, 3215 doi:10.1038/s41467-019-11053-8.

Molina-Gonzalez, I. and V.E. Miron, Astrocytes in myelination and remyelination. Neurosci Lett, 2019. 713: p. 134532 doi.org/10.1016/j.neulet.2019.134532

Multiple Sclerosis

myelin regeneration

astrocyte function

Nrf2

demyelination

oligodendrocytes

Transcriptional analysis of astrocytes reveals protective functions during remyelination

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy