Abstract
Myelin repair in the adult central nervous system (CNS) is driven by successful differentiation of resident oligodendroglial precursor cells (OPCs) and thus constitutes a neurodegenerative process capable to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis (MS). The human endogenous retrovirus type W (HERV-W) represents an MS-specific pathogenic entity, and its envelope (ENV) protein was previously identified as a negative regulator of OPC maturation—hence, it is of relevance in the context of diminished myelin repair. We here focused on the activity of the ENV protein and investigated how it can be neutralized for improved remyelination. ENV-mediated activation of toll like receptor 4 (TLR4) increases inducible nitric oxide synthase (iNOS) expression, prompts nitrosative stress, and results in myelin-associated deficits, such as decreased levels of oligodendroglial maturation marker expression and morphological alterations. The intervention of TLR4 surface expression represents a potential means to rescue such ENV-dependent deficits. To this end, the rescue capacity of specific substances, either modulating V-ATPase activity or myeloid differentiation 2 (MD2)-mediated TLR4 glycosylation status, such as compound 20 (C20), L48H437, or folimycin, was analyzed, as these processes were demonstrated to be relevant for TLR4 surface expression. We found that pharmacological treatment can rescue the maturation arrest of oligodendroglial cells and their myelination capacity and can prevent iNOS induction in the presence of the ENV protein. In addition, downregulation of TLR4 surface expression was observed. Furthermore, mitochondrial integrity crucial for oligodendroglial cell differentiation was affected in the presence of ENV and ameliorated upon pharmacological treatment. Our study, therefore, provides novel insights into possible means to overcome myelination deficits associated with HERV-W ENV-mediated myelin deficits.
Highlights
Multiple sclerosis (MS) is an autoimmune disease of the adult central nervous system (CNS) resulting in the loss of mature oligodendrocytes and their myelin sheaths subsequently leading to neurodegeneration (Lassmann, 2018)
As the myelination process is dependent on high metabolic turnover, which is maintained by mitochondria the essential organelles regulating energy production through oxidative phosphorylation (Tepavcevic, 2021), we revealed for the first time unbalanced mitochondrial homeostasis in the presence of the ENV protein likely to contribute to their impaired myelination activity (Barcelos et al, 2019; Maiuolo et al, 2020)
Since it was recently demonstrated that L48H37, folimycin, and compound 20 (C20) are able to interfere with toll like receptor 4 (TLR4) signaling (Eswarappa et al, 2008; Wang et al, 2015; Zhang et al, 2016), decreasing stress reaction within macrophages, we hypothesized that these substances could stabilize and/or rescue oligodendroglial homeostasis and differentiation in the presence of ENV protein
Summary
Multiple sclerosis (MS) is an autoimmune disease of the adult central nervous system (CNS) resulting in the loss of mature oligodendrocytes and their myelin sheaths subsequently leading to neurodegeneration (Lassmann, 2018). The curcumin derivate [1-ethyl3,5-bis (3,4,5-trimethoxybenzylidene) piperidin-4-one] L48H37, folimycin (concanamycin A) a macrolide antibiotic agent, and the small molecule compound 20 (C20; chalcone derivate that contains the moiety of (E)-4-phenylbut-3-en-2-one) were previously demonstrated to reduce TLR4 cell surface expression in macrophages decreasing nitrosative stress reactions and the production of proinflammatory cytokines, respectively (Eswarappa et al, 2008; Wang et al, 2015; Zhang et al, 2016) Applying these substances to OPCs, we found that oligodendroglial cell differentiation and internode formation can be stabilized in the presence of ENV to various degrees. Our study sheds light on a plausible correlation between ENV-dependent nitrosative stress inductions affecting oligodendroglial energy homeostasis that can be reversed via specific pharmacological stimulation, revealing new subcellular mechanisms that could provide therapeutic targets for upcoming regenerative MS therapies
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