Written by Miyako Rogers, Science Writer
A recent multi-omics study, published in Cell, investigated the activation states of oligodendrocytes (OL) in multiple sclerosis (MS) and Alzheimer’s disease (AD). This study used single-cell RNAseq data to identify 3 distinct disease-associated OL activation states. Researchers then used spatial transcriptomics to map out the spread of disease-associated OLs. The study also revealed similarities and differences between mouse models and humans in MS and AD.
Oligodendrocytes: An underappreciated glial cell
Oligodendrocytes are found in the white matter of the brain. They generate myelin for fast transmission of signals in neurons and provide metabolic support for axons. Studies have already shown that loss of myelin and OLs contributes to the pathogenesis of MS. But loss of white matter and myelin has also been observed in other neurodegenerative diseases, particularly Alzheimer’s Disease. Despite this, OLs have received markedly less attention than their glial cell counterparts, especially microglia, which have been studied thoroughly.
An integrative multi-omics approach
Researchers performed an integrative single-cell analysis of OL lineages across a wide-range of AD and MS models. They then validated their findings with in situ hybridization studies, and used spatial transcriptomics to observe the distribution of OLs relative to induced cuprizone lesions; a white matter myelination model. They then performed analysis on human single-nucleus RNA-sequencing datasets from 3 different MS studies, and 6 different AD studies, to investigate which aspects of OLs were translated from the mouse models to humans.
New insights into oligodendrocyte transcription profiles
Researchers revealed 3 major OL transcriptional states across multiple AD and MS models, one of which was universally induced across all analysed models. This OL type, called DA1, was found to upregulate the expression of immune regulatory molecules, such as cytokines, major-histocompatibility complexes, and complement proteins. DA2 was another OL type identified, which upregulated pathways involved in OL survival, including the EIF2 signalling pathway. EIF2B loss-of-function mutations have been observed in patients with vanishing white matter disease, which is a disease where not enough myelin is produced. The third OL type identified were IFN OLs, which were OLs expressing interferon genes, which are involved in the inflammatory response.
Spatial-transcriptomic analysis of OLs in the corpus callosum showed that all disease-associated OLs were established outside the lesion area during demyelination. However, over time, the process of remyelination takes place, and some interesting observations were made. Unlike the other OLs, DA1 OLs persisted and spread into the lesion site (Figure 2). This suggests that during the recovery process, newly created OLs do not return to their normal transcriptional state – in fact, they adopt this disease-associated transcriptional profile.
Finally, snRNA-seq studies showed that MS OLs share common features with respective mouse models. However, AD OLs were largely distinct from those observed in mice. This could explain the troubles translating preclinical research findings into clinical studies seen in AD research.
Future directions
This study has revealed new insights into the role oligodendrocytes play in neurodegenerative processes and identified 3 major disease-associated oligodendrocyte states implicated in MS and AD. This has huge implications into our understanding of, and potential treatment targets, for these diseases. Furthermore, to accompany this study, researchers created an online resource. This resource is a comprehensive catalogue of oligodendrocyte activation states and allows users to query genes and find comprehensive information about the gene, including multi-omics data and whether it’s found in human or mouse models.
