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Key Points Remyelination is a spontaneous regenerative process in the adult mammalian CNS in which new oligodendrocytes and myelin sheaths are generated from a widespread population of adult progenitor cells. Remyelination involves the distinct stages of progenitor activation, recruitment (proliferation and migration) and differentiation into mature myelin-sheath-forming oligodendrocytes: each is orchestrated by a complex network of cells and signalling molecules. The efficiency of remyelination declines progressively with adult ageing, a phenomenon that has a profound bearing on the natural history of chronic demyelinating diseases such as multiple sclerosis, although experimental studies have revealed that the effects of age are reversible. Remyelination is neuroprotective, limiting the axonal degeneration that follows demyelination. Restoring remyelination is therefore an important therapeutic goal so as to prevent neurodegeneration and progressive disability in multiple sclerosis and other myelin diseases. Insights into the mechanism governing remyelination and an increasing number of high-throughput screening platforms have led to the identification of a number of drug targets for the pharmacological enhancement of remyelination, some of which have entered clinical trials. Advances in the generation of large numbers of human stem and progenitor cells, coupled with compelling preclinical data, have opened up new opportunities for cell-based remyelination therapies, especially for the leucodystrophies. Promoting remyelination may be an effective therapeutic strategy for various disorders that are characterized by a loss of myelin, including multiple sclerosis. In this Review, Franklin and ffrench-Constant discuss recent developments in our understanding of remyelination and the efforts that are underway to enhance this process. Although the core concept of remyelination — based on the activation, migration, proliferation and differentiation of CNS progenitors — has not changed over the past 20 years, our understanding of the detailed mechanisms that underlie this process has developed considerably. We can now decorate the central events of remyelination with a host of pathways, molecules, mediators and cells, revealing a complex and precisely orchestrated process. These advances have led to recent drug-based and cell-based clinical trials for myelin diseases and have opened up hitherto unrecognized opportunities for drug-based approaches to therapeutically enhance remyelination.

Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing–remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2 -expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions. Single-cell RNA sequencing was used to construct a map of gene expression in lesions from brains of patients with multiple sclerosis, revealing distinct lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation.

Multiple sclerosis (MS) can be divided into four phenotypes based on clinical evolution. The pathophysiological boundaries of these phenotypes are unclear, limiting treatment stratification. Machine learning can identify groups with similar features using multidimensional data. Here, to classify MS subtypes based on pathological features, we apply unsupervised machine learning to brain MRI scans acquired in previously published studies. We use a training dataset from 6322 MS patients to define MRI-based subtypes and an independent cohort of 3068 patients for validation. Based on the earliest abnormalities, we define MS subtypes as cortex-led, normal-appearing white matter-led, and lesion-led. People with the lesion-led subtype have the highest risk of confirmed disability progression (CDP) and the highest relapse rate. People with the lesion-led MS subtype show positive treatment response in selected clinical trials. Our findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and may be used to define groups of patients in interventional trials. Multiple sclerosis is a heterogeneous progressive disease. Here, the authors use an unsupervised machine learning algorithm to determine multiple sclerosis subtypes, progression, and response to potential therapeutic treatments based on neuroimaging data.

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes demyelination, axonal degeneration and astrogliosis, resulting in progressive neurological disability. Fuelled by an evolving understanding of MS immunopathogenesis, the range of available immunotherapies for clinical use has expanded over the past two decades. However, MS remains an incurable disease and even targeted immunotherapies often fail to control insidious disease progression, indicating the need for new and exceptional therapeutic options beyond the established immunological landscape. In this Review, we highlight such non-canonical targets in preclinical MS research with a focus on five highly promising areas: oligodendrocytes; the blood–brain barrier; metabolites and cellular metabolism; the coagulation system; and tolerance induction. Recent findings in these areas may guide the field towards novel targets for future therapeutic approaches in MS.Multiple sclerosis (MS) is an immune-mediated neurological disorder featuring central nervous system demyelination. Increasing understanding of the complex pathophysiology of this disease has led to considerable expansion of the MS therapeutic toolbox over the past 20 years, but substantial limitations remain. In this Review, Sven Meuth and colleagues highlight promising non-classical targets for MS that could provide fruitful avenues for future therapies.

As resident macrophages of the CNS, microglia are critical immune effectors of inflammatory lesions and associated neural dysfunctions. In multiple sclerosis (MS) and its animal models, chronic microglial inflammatory activity damages myelin and disrupts axonal and synaptic activity. In contrast to these detrimental effects, the potent phagocytic and tissue-remodelling capabilities of microglia support critical endogenous repair mechanisms. Although these opposing capabilities have long been appreciated, a precise understanding of their underlying molecular effectors is only beginning to emerge. Here, we review recent advances in our understanding of the roles of microglia in animal models of MS and demyelinating lesions and the mechanisms that underlie their damaging and repairing activities. We also discuss how the structured organization and regulation of the genome enables complex transcriptional heterogeneity within the microglial cell population at demyelinating lesions.Microglia are detected in active lesions in multiple sclerosis (MS) and research in animal models has suggested diverse roles for these cells in neural damage and repair. Gosselin and colleagues discuss the mechanisms through which microglia contribute to neuropathology and the molecular mechanisms that regulate their function in demyelinating conditions.

The repair of inflamed, demyelinated lesions as in multiple sclerosis (MS) necessitates the clearance of cholesterol-rich myelin debris by microglia/macrophages and the switch from a pro-inflammatory to an anti-inflammatory lesion environment. Subsequently, oligodendrocytes increase cholesterol levels as a prerequisite for synthesizing new myelin membranes. We hypothesized that lesion resolution is regulated by the fate of cholesterol from damaged myelin and oligodendroglial sterol synthesis. By integrating gene expression profiling, genetics and comprehensive phenotyping, we found that, paradoxically, sterol synthesis in myelin-phagocytosing microglia/macrophages determines the repair of acutely demyelinated lesions. Rather than producing cholesterol, microglia/macrophages synthesized desmosterol, the immediate cholesterol precursor. Desmosterol activated liver X receptor (LXR) signaling to resolve inflammation, creating a permissive environment for oligodendrocyte differentiation. Moreover, LXR target gene products facilitated the efflux of lipid and cholesterol from lipid-laden microglia/macrophages to support remyelination by oligodendrocytes. Consequently, pharmacological stimulation of sterol synthesis boosted the repair of demyelinated lesions, suggesting novel therapeutic strategies for myelin repair in MS. Efficient repair of demyelinated CNS lesions involves the resolution of inflammation and induction of remyelination. Berghoff et al. show that sterol synthesis in microglia is key to both processes, which can be supported by squalene therapy.

Key Points Healthy structural and functional brain networks are characterized by a cost-effective architecture, which has an optimal balance between local and global connectivity, and a hierarchical modular structure. Normal brain-network organization arises during development under genetic control and is correlated with cognitive function. Local brain lesions give rise to widespread changes to networks, whereas global brain disorders preferentially affect highly connected hub regions. In many neurological disorders, the most consistent changes concern a breakdown of the hierarchical modular structure and, in particular, a loss of highly connected hub areas. The pattern of network changes in neurological disorders may be explained by a hypothetical scenario of 'hub overload and failure'. The application of network science to several common neurological disorders challenges the idea that these disorders are either 'local' or 'global'. In this Review, Kees Stam proposes a model of hub overload and failure as a possible final common pathway in diverse neurological disorders. Modern network science has revealed fundamental aspects of normal brain-network organization, such as small-world and scale-free patterns, hierarchical modularity, hubs and rich clubs. The next challenge is to use this knowledge to gain a better understanding of brain disease. Recent developments in the application of network science to conditions such as Alzheimer's disease, multiple sclerosis, traumatic brain injury and epilepsy have challenged the classical concept of neurological disorders being either 'local' or 'global', and have pointed to the overload and failure of hubs as a possible final common pathway in neurological disorders.

Oligodendrocyte pathology is increasingly implicated in neurodegenerative diseases as oligodendrocytes both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination 1 , which suggests that other factors contribute to this variability. One such factor may be oligodendrocyte heterogeneity. Not all oligodendrocytes are the same—those from the mouse spinal cord inherently produce longer myelin sheaths than those from the cortex 2 , and single-cell analysis of the mouse central nervous system identified further differences 3 , 4 . However, the extent of human oligodendrocyte heterogeneity and its possible contribution to MS pathology remain unknown. Here we performed single-nucleus RNA sequencing from white matter areas of post-mortem human brain from patients with MS and from unaffected controls. We identified subclusters of oligodendroglia in control human white matter, some with similarities to mouse, and defined new markers for these cell states. Notably, some subclusters were underrepresented in MS tissue, whereas others were more prevalent. These differences in mature oligodendrocyte subclusters may indicate different functional states of oligodendrocytes in MS lesions. We found similar changes in normal-appearing white matter, showing that MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important for understanding disease progression and developing therapeutic approaches. Single-nucleus RNA sequencing analysis identifies different subclusters of oligodendroglia in white matter from individuals with multiple sclerosis compared with controls, and these differences may be important for understanding disease progression.

Blood vessels in the CNS form a specialized and critical structure, the blood–brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells with peripheral endothelial cells. We also assessed the regulation of CNS endothelial gene expression in models of stroke, multiple sclerosis, traumatic brain injury and seizure, each having profound BBB disruption. We found that although each is caused by a distinct trigger, they exhibit strikingly similar endothelial gene expression changes during BBB disruption, comprising a core BBB dysfunction module that shifts the CNS endothelial cells into a peripheral endothelial cell-like state. The identification of a common pathway for BBB dysfunction suggests that targeting therapeutic agents to limit it may be effective across multiple neurological disorders.

Ischaemia damages nerve myelin by depriving neurons and their myelinating oligodendrocytes of oxygen and glucose; here it is shown that ischaemic damage is caused through the H + -dependent activation of TRPA1 channels, and not via glutamate receptors of the NMDA type, as previously thought, providing a new mechanism and promising therapeutic targets for diseases as diverse and prevalent as cerebral palsy, spinal cord injury, stroke and multiple sclerosis. TRP channels damaged in ischaemia Fast nerve conduction relies on the insulating sheaths of myelin produced by glial cells — oligodendrocytes — of the white matter. These cells can be damaged by deprivation of blood oxygen (ischaemia) during stroke and other circulatory disturbances. David Attwell and colleagues show that ischaemic damage to oligodendrocytes causes elevation of intracellular Ca 2+ levels through H + -dependent activation of TRPA1 receptors, and not via glutamate receptors of the NMDA type, as previously thought. The results provide a new mechanism and promising therapeutic targets for diseases as diverse and prevalent as cerebral palsy, spinal cord injury, stroke and multiple sclerosis. The myelin sheaths wrapped around axons by oligodendrocytes are crucial for brain function. In ischaemia myelin is damaged in a Ca 2+ -dependent manner, abolishing action potential propagation 1 , 2 . This has been attributed to glutamate release activating Ca 2+ -permeable N -methyl- d -aspartate (NMDA) receptors 2 , 3 , 4 . Surprisingly, we now show that NMDA does not raise the intracellular Ca 2+ concentration ([Ca 2+ ] i ) in mature oligodendrocytes and that, although ischaemia evokes a glutamate-triggered membrane current 4 , this is generated by a rise of extracellular [K + ] and decrease of membrane K + conductance. Nevertheless, ischaemia raises oligodendrocyte [Ca 2+ ] i , [Mg 2+ ] i and [H + ] i , and buffering intracellular pH reduces the [Ca 2+ ] i and [Mg 2+ ] i increases, showing that these are evoked by the rise of [H + ] i . The H + -gated [Ca 2+ ] i elevation is mediated by channels with characteristics of TRPA1, being inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout. TRPA1 block reduces myelin damage in ischaemia. These data suggest that TRPA1-containing ion channels could be a therapeutic target in white matter ischaemia.