<scp>C</scp>onditional depletion of <scp>GSK</scp>3b protects oligodendrocytes from apoptosis and lessens demyelination in the acute cuprizone model

Xing, Bin; Brink, Lauren E.; Maers, Kelly; Sullivan, Mara; Bodnar, Richard J.; Stolz, Donna B.; Cambi, Franca

doi:10.1002/glia.23453

Cited by 16 publications

(8 citation statements)

References 52 publications

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“…The respective podocytes were characterized by increased glycogen accumulation [142] as well as preserved cytoskeleton integrity and focal adhesions, reduced mitochondria dysfunction, and diminished pro-inflammatory nuclear factor (NF-)κB activation [141]. Anti-apoptotic effects of GSK3β deficiency have also been observed in murine GSK3β KO oligodendrocytes that are protected from caspase-dependent (but not -independent) apoptosis [144]. Moreover, in heterozygous GSK3β +/mice exhibiting Pam3CSK4-induced peritonitis, the extent of inflammation was significantly lower than in the wildtype and equivalent results have been obtained in chimeric mice possessing GSK3β KO hematopoietic cells [145].…”

Section: Gsk3 Ko Modelsmentioning

confidence: 99%

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

102

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GSK3 has been implicated for years in the regulation of inflammation and addressed in a plethora of scientific reports using a variety of experimental (disease) models and approaches. However, the specific role of GSK3 in the inflammatory process is still not fully understood and controversially discussed. Following a detailed overview of structure, function, and various regulatory levels, this review focusses on the immunoregulatory functions of GSK3, including the current knowledge obtained from animal models. Its impact on pro-inflammatory cytokine/chemokine profiles, bacterial/viral infections, and the modulation of associated pro-inflammatory transcriptional and signaling pathways is discussed. Moreover, GSK3 contributes to the resolution of inflammation on multiple levels, e.g., via the regulation of pro-resolving mediators, the clearance of apoptotic immune cells, and tissue repair processes. The influence of GSK3 on the development of different forms of stimulation tolerance is also addressed. Collectively, the role of GSK3 as a kinase balancing the initiation/perpetuation and the amelioration/resolution of inflammation is highlighted.

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Section: Gsk3 Ko Modelsmentioning

confidence: 99%

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

102

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“…At weeks 3 and 5, oligodendrocyte apoptosis was still ongoing. Although it has been demonstrated that in the cuprizone model oligodendrocyte apoptosis is ongoing for weeks (Hesse et al, 2010;Sanadgol et al, 2017;Xing et al, 2018), we verified this aspect by staining sections with anti-OLIG2 antibodies and inspecting the corpus callosum for the presence of OLIG2 + apoptotic bodies. As demonstrated in Figure 1e, apoptotic bodies decorated by anti-OLIG2 immunoreactivity could be clearly demonstrated at week 3.…”

Section: Sequential Oligodendrocyte Degeneration During Cuprizone-imentioning

confidence: 68%

Cuprizone‐induced graded oligodendrocyte vulnerability is regulated by the transcription factor DNA damage‐inducible transcript 3

Fischbach¹,

Nedelcu²,

Leopold³

et al. 2018

Glia

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Oligodendrocytes are integral to efficient neuronal signaling. Loss of myelinating oligodendrocytes is a central feature of many neurological diseases, including multiple sclerosis (MS). The results of neuropathological studies suggest that oligodendrocytes react with differing sensitivity to toxic insults, with some cells dying early during lesion development and some cells being resistant for weeks. This proposed graded vulnerability has never been demonstrated but provides an attractive window for therapeutic interventions. Furthermore, the biochemical pathways associated with graded oligodendrocyte vulnerability have not been well explored. We used immunohistochemistry and serial block‐face scanning electron microscopy (3D‐SEM) to show that cuprizone‐induced metabolic stress results in an “out of phase” degeneration of oligodendrocytes. Although expression induction of stress response transcription factors in oligodendrocytes occurs within days, subsequent oligodendrocyte apoptosis continues for weeks. In line with the idea of an out of phase degeneration of oligodendrocytes, detailed ultrastructural reconstructions of the axon–myelin unit demonstrate demyelination of single internodes. In parallel, genome wide array analyses revealed an active unfolded protein response early after initiation of the cuprizone intoxication. In addition to the cytoprotective pathways, the pro‐apoptotic transcription factor DNA damage‐inducible transcript 3 (DDIT3) was induced early in oligodendrocytes. In advanced lesions, DDIT3 was as well expressed by activated astrocytes. Toxin‐induced oligodendrocyte apoptosis, demyelination, microgliosis, astrocytosis, and acute axonal damage were less intense in the Ddit3‐null mutants. This study identifies DDIT3 as an important regulator of graded oligodendrocyte vulnerability in a MS animal model. Interference with this stress cascade might offer a promising therapeutic approach for demyelinating disorders.

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“…Our results with HIV‐1 Tat are in accord with the finding that conditional depletion of GSK3β protected myelinating OLs from caspase‐dependent death in the cuprizone demyelination model (Xing et al . ). Although CaMKIIβ levels or activity were not explored in the cuprizone study, it is striking that GSK3β activation is implicated in OL death resulting from these disparate insults.…”

Section: Discussionmentioning

confidence: 97%

Effects of HIV‐1 Tat on oligodendrocyte viability are mediated by CaMKIIβ–GSK3β interactions

Zou

Balinang

Paris

et al. 2019

Journal of Neurochemistry

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Myelin disruptions are frequently reported in human immunodeficiency virus (HIV)‐infected individuals and can occur in the CNS very early in the disease process. Immature oligodendrocytes (OLs) are quite sensitive to toxic increases in [Ca2+]i caused by exposure to HIV‐1 Tat (transactivator of transcription, a protein essential for HIV replication and gene expression), but sensitivity to Tat‐induced [Ca2+]i is reduced in mature OLs. Tat exposure also increased the activity of Ca2+/calmodulin‐dependent kinase IIβ (CaMKIIβ), the major isoform of CaMKII expressed by OLs, in both immature and mature OLs. Since CaMKIIβ is reported to interact with glycogen synthase kinase 3β (GSK3β), and GSK3β activity is implicated in OL apoptosis as well as HIV neuropathology, we hypothesized that disparate effects of Tat on OL viability with maturity might be because of an altered balance of CaMKIIβ–GSK3β activities. Tat expression in vivo led to increased CaMKIIβ and GSK3β activity in multiple brain regions in transgenic mice. In vitro, immature murine OLs expressed higher levels of GSK3β, but much lower levels of CaMKIIβ, than did mature OLs. Exogenous Tat up‐regulated GSK3β activity in immature, but not mature, OLs. Tat‐induced death of immature OLs was rescued by the GSK3β inhibitors valproic acid or SB415286, supporting involvement of GSK3β signaling. Pharmacologically inhibiting CaMKIIβ increased GSK3β activity in Tat‐treated OLs, and genetically knocking down CaMKIIβ promoted death in mature OL cultures treated with Tat. Together, these results suggest that the effects of Tat on OL viability are dependent on CaMKIIβ–GSK3β interactions, and that increasing CaMKIIβ activity is a potential approach for limiting OL/myelin injury with HIV infection.

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Conditional depletion of GSK3b protects oligodendrocytes from apoptosis and lessens demyelination in the acute cuprizone model

Cited by 16 publications

References 52 publications

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Cuprizone‐induced graded oligodendrocyte vulnerability is regulated by the transcription factor DNA damage‐inducible transcript 3

Effects of HIV‐1 Tat on oligodendrocyte viability are mediated by CaMKIIβ–GSK3β interactions

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