Regulation of sirtuin expression in autoimmune neuroinflammation: Induction of SIRT1 in oligodendrocyte progenitor cells

Prozorovski, Timour; Ingwersen, Jens; Lukas, Denise; Göttle, Peter; Koop, Barbara; Graf, Jonas; Schneider, Reiner; Franke, Kristin; Schumacher, Stefan; Britsch, Stefan; Hartung, Hans‐Peter; Küry, Patrick; Berndt, Carsten; Aktaş, Orhan

doi:10.1016/j.neulet.2019.04.007

Cited by 23 publications

(27 citation statements)

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“…In accordance, specific inactivation of SIRT1 by means of the small molecule inhibitor EX-527, a protein deacetylase implicated in energy metabolism, increased the production of new NSC-derived OPCs in the adult mouse brain [136]. Likewise, a similar promoting effect could also be attributed to this molecule in the OPC context [137]. Furthermore, activation of the fibroblast growth factor receptor-3 (FGFR3) signaling was recently shown to redirect the differentiation of SVZ-derived NSCs from neuronal to oligodendroglial lineage, hence, promoting remyelination [138].…”

Section: Regulators Of Glia Cell Fate: Avenues To Adjust Aberrant Whimentioning

confidence: 78%

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

Reiche

Küry

Göttle

2019

Cells

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Down syndrome (DS), or trisomy 21, is the most prevalent chromosomal anomaly accounting for cognitive impairment and intellectual disability (ID). Neuropathological changes of DS brains are characterized by a reduction in the number of neurons and oligodendrocytes, accompanied by hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS, but underestimated the role of glial cells as pathogenic players. Aberrant or impaired differentiation within the oligodendroglial lineage and altered white matter functionality are thought to contribute to central nervous system (CNS) malformations. Given that white matter, comprised of oligodendrocytes and their myelin sheaths, is vital for higher brain function, gathering knowledge about pathways and modulators challenging oligodendrogenesis and cell lineages within DS is essential. This review article discusses to what degree DS-related effects on oligodendroglial cells have been described and presents collected evidence regarding induced cell-fate switches, thereby resulting in an enhanced generation of astrocytes. Moreover, alterations in white matter formation observed in mouse and human post-mortem brains are described. Finally, the rationale for a better understanding of pathways and modulators responsible for the glial cell imbalance as a possible source for future therapeutic interventions is given based on current experience on pro-oligodendroglial treatment approaches developed for demyelinating diseases, such as multiple sclerosis.

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Section: Regulators Of Glia Cell Fate: Avenues To Adjust Aberrant Whimentioning

confidence: 78%

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

Reiche

Küry

Göttle

2019

Cells

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“…Several studies have recently shown that SIRT1 regulates the proliferation of OPCs (18)(19)(20). Xiang et al have shown that overexpression of SIRT1 in cultured mouse OPCs promotes their differentiation toward OLGs through the upregulation of peroxisome-proliferator-activated receptor gamma co-activator 1 alpha (PGC1α), and this process is inhibited in the presence of mutant huntingtin (40).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, SIRT1 inactivation in the CNS enhances the rate of remyelination in demyelinating injury and minimizes the severity of clinical symptoms in chronic experimental allergic encephalomyelitis (EAE) (18). A recent study in EAE mice has also found that SIRT1 is co-localized with NG2 + and platelet-derived growth factor receptor alpha (PDGFRα) + OPCs in cerebellar white matter in close proximity to demyelinating areas during the chronic stage of the disease, and SIRT1 inhibition results in an enhanced proliferation of OPCs without affecting their ability to differentiate (20). These findings suggest that OPC differentiation occurs in the absence of SIRT1 and that the role of SIRT1 in OPC proliferation may be region-and disease-specific.…”

Section: Discussionmentioning

confidence: 99%

“…We have also shown that SIRT1 expression is reduced in peripheral blood Abbreviations: CNS, central nervous system; CSPG4, chondroitin sulfate proteoglycan 4; EAE, experimental autoimmune encephalomyelitis; ERK, extracellular-regulated kinase; MBP, myelin basic protein; MS, multiple sclerosis; NG2, neuron glial antigen 2; OLG, oligodendrocyte; OPC, oligodendrocyte precursor cell; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLP, proteolipid protein; p-SIRT1, phosphorylated SIRT1; SIRT1, sirtuin 1. mononuclear cells of MS patients during relapses and in those who do not respond to treatment with glatiramer acetate, a disease-modifying drug used for treating MS, suggesting that SIRT1 could serve as a biomarker of disease activity and patient responsiveness to therapy (15,17). Other studies have indicated that SIRT1 is involved in OPCs proliferation and differentiation toward OLGs during pathological conditions (18)(19)(20). However, it is not currently known whether SIRT1 is implicated in the OLG cell cycle activation induced by sublytic C5b-9 or whether complement activation and sublytic C5b-9 have any effect on SIRT1.…”

Section: Introductionmentioning

confidence: 99%

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Histone Deacetylase SIRT1 Mediates C5b-9-Induced Cell Cycle in Oligodendrocytes

et al. 2020

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Sublytic levels of C5b-9 increase the survival of oligodendrocytes (OLGs) and induce the cell cycle. We have previously observed that SIRT1 co-localizes with surviving OLGs in multiple sclerosis (MS) plaques, but it is not yet known whether SIRT1 is involved in OLGs survival after exposure to sublytic C5b-9. We have now investigated the role of SIRT1 in OLGs differentiation and the effect of sublytic levels of C5b-9 on SIRT1 and phosphorylated-SIRT1 (Ser27) expression. We also examined the downstream effects of SIRT1 by measuring histone H3 lysine 9 trimethylation (H3K9me3) and the expression of cyclin D1 as a marker of cell cycle activation. OLG progenitor cells (OPCs) purified from the brain of rat pups were differentiated in vitro and treated with sublytic C5b-9 or C5b6. To investigate the signaling pathway activated by C5b-9 and required for SIRT1 expression, we pretreated OLGs with a c-jun antisense oligonucleotide, a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002), and a protein kinase C (PKC) inhibitor (H7). Our data show a significant reduction in phospho-SIRT1 and SIRT1 expression during OPCs differentiation, associated with a decrease in H3K9me3 and a peak of cyclin D1 expression in the first 24 h. Stimulation of OLGs with sublytic C5b-9 resulted in an increase in the expression of SIRT1 and phospho-SIRT1, H3K9me3, cyclin D1 and decreased expression of myelin-specific genes. C5b-9-stimulated SIRT1 expression was significantly reduced after pretreatment with c-jun antisense oligonucleotide, H7 or LY294002. Inhibition of SIRT1 with sirtinol also abolished C5b-9-induced DNA synthesis. Taken together, these data show that induction of SIRT1 expression by C5b-9 is required for cell cycle activation and is mediated through multiple signaling pathways.

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“…The elevated level in the generation of oligodendrocyte progenitor cells (OPCs) was also reported in NPC-specific knockout of SIRT1 in mice (Rafalski et al, 2013). Furthermore, several studies have shown that SIRT1 inhibition leads to improvement of Table 2 The role of sirtuins in human pathologies or animal models of MS. (Shindler et al, 2007) EAE mouse SRT501 Preservation of axonal density in the spinal cord (Shindler et al, 2010) EAE mouse Genetically SIRT1 overexpression Suppression of EAE symptoms (Nimmagadda et al, 2013) EAE mouse Intravitreal overexpression of SIRT1 Neuroprotection of visual function and RGC survival (McDougald et al, 2018) EAE mouse Increase of SIRT1 expression in GFAP-positive cells around inflammatory lesions (Prozorovski et al, 2008) C57BL/6 mice Resveratrol (SIRT1 activator) Suppression of proliferation in NPCs-differentiation toward astrocyte (Prozorovski et al, 2008) C57BL/6 mice Knockout of SIRT1 Elevated level in OPCs generation (Rafalski et al, 2013) EAE mouse Ex-527 (SIRT1 inhibitor) Induction of remyelination, delay in paralysis onset, inhibition of pro-inflammatory Th17 cells and reduction of infiltration of immune cells into the spinal cord (Lim et al, 2015) EAE mouse Increase in level of transcription of SIRT1 in the CNS during chronic disease stages (Prozorovski et al, 2019) Upregulated level of SIRT1 in nuclei of NG2+ or PDGFRα+ OPCs in demyelinated brain lesions.…”

Section: Sirtuin-1mentioning

confidence: 99%