Remyelination

…lineage cells and their degrees of remyelination, both across different individuals and within each MS patient1. To date, the intrinsic genetic factors that potentially impact OLG-mediated de- and re-myelination in MS lesions,

…pathways within phagocytes to enable remyelination of acute lesion. However, to date it is unclear how chronic progressive disease is linked to lipid metabolic pathways. According to the ‘inside-out’ concept of

In multiple sclerosis (MS), oligodendrocyte (OL) degeneration and subsequent demyelination in the central nervous system (CNS) causes neurological impairment. Monocarboxylate transporter 8 (MCT8) may promote OL maturation and myelination by actively transporting thyroid hormone (TH) into the CNS and thereby facilitating key transcription and metabolomic pathways for myelin biogenesis. Diiodothyropropionic acid (DITPA), a synthetic TH-analog, can be transported into the CNS, independent of MCT8 and may promote OL maturation and myelination. In this study, we investigated the potential of DITPA

…neuronal activity in vivo enhances remyelination in demyelinated lesions (Ortiz et al., 2019, JCI Insight). Here, we investigate whether calcium singal in oligodendroglia play a role in remyelination and whether beha

Schwann cells (SCs) are the principal glia of the peripheral nervous system and are in close contact with axons to ensure a fast propagation of electrical impulses. After nerve injury, myelinating SCs distal to the injury site dedifferentiate into pro-regenerative repair SCs. In a later phase after injury, repair SCs must redifferentiate into myelinating cells to provide a fully functional regenerated nerve. Meyer zu Reckendorf et al. recently showed the important role of metabolic adaptation in SC reprogramming after injury in an ex vivo nerve lesion model. In particular, lipid metabolism dow

Myelin, produced by oligodendrocytes (OLs), is a lipid-rich structure that wraps axons, facilitating the saltatory conduction and providing metabolic support to neurons. Myelin is a highly adaptable structure whose role in regulating synaptic transmission in the healthy and diseased brain have not been extensively examined and may be relevant for understanding neuronal dysfunctions associated with myelin-related disorders. Here, we investigated excitatory (EPSCs) and inhibitory (IPSCs) post-synaptic currents in layer IV of the somatosensory (barrel) cortex using a cuprizone-induced demyelinati

…locomotor impairment after SCI when remyelination was inhibited in young mice (Duncan et al. 2018, Nat. Comm). However, the functional impact of remyelination after SCI at an advanced age is unknown. Here, we assessed the importance of remyelination for locomotor recovery, cognitive function, and anxiety in young (3-5 month) and aged (15-18 month) mice of b

Aims. Interleukin-33 is a protein enhancing Th2 cytokine production, initially described as an alarmin that is released from dying, necrotic cells to affect the immune response. Therefore, we aimed to examine the role of IL-33 in response to both CNS and PNS injury. Methods and Results. Using qPCR, Western blotting, and ELISA assay we showed significant up-regulation of IL-33 in two models of nervous system pathology in response to demyelination of the CNS white matter and sciatic nerve crush. We showed that IL-33 is produced exclusively by non-myelinating oligodendrocytes in the intact white

…during disease progression and remyelination. First, brain RNA-sequencing of healthy, demyelination and remyelination states revealed upregulation of microglia genes involved in inflammation,

Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) marked by myelin degradation. Myelin is a lipid-rich insulating sheath essential for efficient signal transmission and neuronal health. Despite the critical role of demyelination in MS, existing treatments do not halt disease progression or promote myelin regeneration. Recent insights from our lab underscore microRNA-145 (miR-145) as a pivotal factor hindering oligodendrocyte production, with elevated levels detected in chronic lesions of secondary progressive MS post-mortem brain tissue. To unveil t

Oligodendrocytes, the myelinating glial cells of the central nervous system (CNS), surround axons with their membrane extensions, forming the myelin sheath. Loss of oligodendrocytes and/or myelin (demyelination) occurs in traumatic brain injury or pathologies such as multiple sclerosis. Since, there is no specific treatment for demyelination; we are interested in enhancing myelin endogenous repair. We focus our work on A Disintegrin and Metalloprotease (ADAM) 10, the major CNS α-secretase, which generates the neuroprotective soluble fragment sAPPα via cleavage of the Amyloid Precursor Protein

Adenosine A1 receptor (A1AR) signaling exerts important functions in the central nervous system (CNS). Among all CNS cell types, oligodendrocyte (OL) lineage cells possess the highest A1AR expression levels. However, in vivo data regarding the functions of A1ARs in OL lineage cells remain elusive. Here, we first generated NG2-CreERT2xA1ARfl/fl conditional knockout (cKO) mice to specifically delete A1ARs from oligodendrocyte precursor cells (OPCs) upon tamoxifen administration. Immunohistochemical analysis for OL lineage markers PDGFRα, APC CC1, as well as BrdU incorporation detected unaltered

The transcriptional corepressors NCOR1 and NCOR2 are part of a multiprotein complex that downregulates Jun and triggers the transcription of myelin genes in cultured Schwann cells (SC) (Gomis-Coloma et al., 2018). Both corepressors are also expressed in oligodendrocyte lineage cells, both oligodendrocytes (OL), and in OL precursor cells (OPCs), suggesting that they might contribute to their development and function (Castelo-Branco et al., 2014). Using genetically modified mice we have previously shown that they are dispensable for myelin development in the peripheral nervous system (PNS). In t

Toll-Like Receptor 4 (TLR4) is a relevant actor for innate immunity involved in inflammatory responses in Multiple Sclerosis (MS) and other diseases. The currently available therapeutic arsenal to treat MS is composed of immunomodulators but, to date, there are no (re)myelinating drugs available in clinics. In the present work, we study the effect of TLR4 inhibition in different animal models of MS.The experimental autoimmune encephalomyelitis (EAE) model was used to evaluate the effect of TLR4 inhibition on reducing the inflammatory component. A more direct effect on oligodendroglia was studi

…demyelination, axonal damage and remyelination, however the exact mechanisms controlling their transformation towards a protective or devastating phenotype during the disease progression remains largely unknown until now. We wish to

Synchronization of neural activity is a fundamental component of information processing in the nervous system. Precise axonal conduction is required for correlated spiking activity between pairs of neurons at the millisecond timescale. Previous studies report that myelin loss results in deficient action potential propagation and a loss of population synchronization in the gamma band. Loss of myelination in demyelinating diseases like multiple sclerosis (MS) results in impaired motor function in patients with MS. However, a deeper understanding of how demyelination alters the timing, synchrony

…is to prevent axons degenerating by remyelination. Since the discovery that

Our goal is to understand why myelin repair fails in multiple sclerosis and to develop regenerative medicines for the nervous system. A central obstacle for progress in this area has been the complex biology underlying the response to CNS injury. Acute CNS damage is followed by a multicellular response that encompasses different cell types and spans different scales. Currently, we do not understand which factors determines lesion recovery. Failure of inflammation to resolve is a key underlying reason of poor regeneration, and one focus is therefore on the biology of microglia during de- and re