Involvement of fractin in TGF‐β‐induced apoptosis in oligodendroglial progenitor cells

Schulz, Ramona; Vogel, Tanja; Mashima, Tetsuo; Tsuruo, Takashi; Krieglstein, Kerstin

doi:10.1002/glia.20875

Cited by 18 publications

(14 citation statements)

References 38 publications

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“…While calpain may cleave actin in addition to caspase-3, fractin is a specific 32 kD product produced solely by the cleavage of actin by caspase 3 as reported by several previous studies that involved: (a) the immunolabeling of Hirano bodies, which are eosinophilic rod-shaped inclusions found primarily in CA1 hippocampal neurons in aged animals and in the brains of Alzheimer's disease patients [53]; (b) a demonstration that the caspase-specific cleavage product fractin is produced in oligodendroglial cells during TGF-beta-mediated apoptosis [54]; (c) distinguishing between calpain and caspase-3 activity by staining for fractin in excitoxicity-induced neurodegeneration in adult brains [55] and in Alzheimer neuropathology [56], [58]. During apoptosis, beta actin is cleaved by activated caspase 3 between Asp244 and Gly245.…”

Section: Discussionsupporting

confidence: 60%

Degeneration of Axotomized Projection Neurons in the Rat dLGN: Temporal Progression of Events and Their Mitigation by a Single Administration of FGF2

2012

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Removal of visual cortex in the rat axotomizes projection neurons in the dorsal lateral geniculate nucleus (dLGN), leading to cytological and structural changes and apoptosis. Biotinylated dextran amine was injected into the visual cortex to label dLGN projection neurons retrogradely prior to removing the cortex in order to quantify the changes in the dendritic morphology of these neurons that precede cell death. At 12 hours after axotomy we observed a loss of appendages and the formation of varicosities in the dendrites of projection neurons. During the next 7 days, the total number of dendrites and the cross-sectional areas of the dendritic arbors of projection neurons declined to about 40% and 20% of normal, respectively. The response of dLGN projection neurons to axotomy was asynchronous, but the sequence of structural changes in individual neurons was similar; namely, disruption of dendrites began within hours followed by cell soma atrophy and nuclear condensation that commenced after the loss of secondary dendrites had occurred. However, a single administration of fibroblast growth factor-2 (FGF2), which mitigates injury-induced neuronal cell death in the dLGN when given at the time of axotomy, markedly reduced the dendritic degeneration of projection neurons. At 3 and 7 days after axotomy the number of surviving dendrites of dLGN projection neurons in FGF-2 treated rats was approximately 50% greater than in untreated rats, and the cross-sectional areas of dendritic arbors were approximately 60% and 50% larger. Caspase-3 activity in axotomized dLGN projection neurons was determined by immunostaining for fractin (fractin-IR), an actin cleavage product produced exclusively by activated caspase-3. Fractin-IR was seen in some dLGN projection neurons at 36 hours survival, and it increased slightly by 3 days. A marked increase in reactivity was seen by 7 days, with the entire dLGN filled with dense fractin-IR in neuronal cell somas and dendrites.

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Section: Discussionsupporting

confidence: 60%

Degeneration of Axotomized Projection Neurons in the Rat dLGN: Temporal Progression of Events and Their Mitigation by a Single Administration of FGF2

2012

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“…There is evidence that cells in the OL lineage can be stained with antibodies to fractin when they are undergoing apoptotic degeneration [37,38]. Therefore, we stained sections adjacent to those we had stained for AC3 or silver, with antibodies to fractin, and found that fractin staining readily detected a similar number of cells in the same WM locations [Figure 1c], and the appearance of these degenerating WM cells when stained with fractin was very similar to their appearance when stained with AC3 or silver [compare Figure 1a,b,c].…”

Section: Resultsmentioning

confidence: 99%

“…In order to confirm that these cells were dying we applied the DeOlmos cupric silver stain, which selectively stains cells that are dead or dying [1,64]. We also performed IHC staining with antibodies to fractin, a breakdown product of actin that is generated by the proteolytic action of caspase enzymes in OLs that are undergoing apoptotic degeneration [37,38]. To clarify the identity and maturational status of these AC3-positive WM cells, we used immunofluorescent double staining for AC3 or fractin (markers for apoptosis) and GFAP (marker for astrocytes), Iba1 (marker for microglia and macrophages) [35], platelet-derived growth factor receptor alpha (PDGFRα) (marker for OL progenitors) [35,39,40], myelin basic protein (MBP) (marker for premyelinating and myelinating OLs) [40], and neuN (marker for neurons).…”

Section: Methodsmentioning

confidence: 99%

Alcohol-induced apoptosis of oligodendrocytes in the fetal macaque brain

Creeley

Dikranian

Johnson

et al. 2013

acta neuropathol commun

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BackgroundIn utero exposure of the fetal non-human primate (NHP) brain to alcohol on a single occasion during early or late third-trimester gestation triggers widespread acute apoptotic death of cells in both gray and white matter (WM) regions of the fetal brain. In a prior publication, we documented that the dying gray matter cells are neurons, and described the regional distribution and magnitude of this cell death response. Here, we present new findings regarding the magnitude, identity and maturational status of the dying WM cells in these alcohol-exposed fetal NHP brains.ResultsOur findings document that the dying WM cells belong to the oligodendrocyte (OL) lineage. OLs become vulnerable when they are just beginning to generate myelin basic protein in preparation for myelinating axons, and they remain vulnerable throughout later stages of myelination. We found no evidence linking astrocytes, microglia or OL progenitors to this WM cell death response. The mean density (profiles per mm3) of dying WM cells in alcohol-exposed brains was 12.7 times higher than the mean density of WM cells dying by natural apoptosis in drug-naive control brains.ConclusionsIn utero exposure of the fetal NHP brain to alcohol on a single occasion triggers widespread acute apoptotic death of neurons (previous study) and of OLs (present study) throughout WM regions of the developing brain. The rate of OL apoptosis in alcohol-exposed brains was 12.7 times higher than the natural OL apoptosis rate. OLs become sensitive to the apoptogenic action of alcohol when they are just beginning to generate constituents of myelin in their cytoplasm, and they remain vulnerable throughout later stages of myelination. There is growing evidence for a similar apoptotic response of both neurons and OLs following exposure of the developing brain to anesthetic and anticonvulsant drugs. Collectively, this body of evidence raises important questions regarding the role that neuro and oligo apoptosis may play in the human condition known as fetal alcohol spectrum disorder (FASD), and also poses a question whether other apoptogenic drugs, although long considered safe for pediatric/obstetric use, may have the potential to cause iatrogenic FASD-like developmental disability syndromes.

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“…Interestingly, fractin has been shown to be present in the brains of preterms with periventricular leukomalacia 75. The cleavage of actin into fractin may be not only an apoptotic marker but also a functional player in the apoptotic pathway 76. The protective role of Lf may also be mediated by its ability to maintain the level of P-AKT higher after HI.…”

Section: Discussionmentioning

confidence: 99%

Lactoferrin during lactation protects the immature hypoxic‐ischemic rat brain

Looij

Ginet

Chatagner

et al. 2014

Ann Clin Transl Neurol

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ObjectiveLactoferrin (Lf) is an iron-binding glycoprotein secreted in maternal milk presenting anti-inflammatory and antioxidant properties. It shows efficient absorption into the brain from nutritional source. Brain injury frequently resulting from cerebral hypoxia-ischemia (HI) has a high incidence in premature infants with ensuing neurodevelopmental disabilities. We investigated the neuroprotective effect of maternal nutritional supplementation with Lf during lactation in a rat model of preterm HI brain injury using magnetic resonance imaging (MRI), brain gene, and protein expression.MethodsModerate brain HI was induced using unilateral common carotid artery occlusion combined with hypoxia (6%, 30 min) in the postnatal day 3 (P3) rat brain (24–28 weeks human equivalent). High-field multimodal MRI techniques were used to investigate the effect of maternal Lf supplementation through lactation. Expression of cytokine coding genes (TNF-α and IL-6), the prosurvival/antiapoptotic AKT protein and caspase-3 activation were also analyzed in the acute phase after HI.ResultsMRI analysis demonstrated reduced cortical injury in Lf rats few hours post-HI and in long-term outcome (P25). Lf reduced HI-induced modifications of the cortical metabolism and altered white matter microstructure was recovered in Lf-supplemented rats at P25. Lf supplementation significantly decreased brain TNF-α and IL-6 gene transcription, increased phosphorylated AKT levels and reduced activation of caspase-3 at 24 h post-injury.InterpretationLf given through lactation to rat pups with cerebral HI injury shows neuroprotective effects on brain metabolism, and cerebral gray and white matter recovery. This nutritional intervention may be of high interest for the clinical field of preterm brain neuroprotection.

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Involvement of fractin in TGF‐β‐induced apoptosis in oligodendroglial progenitor cells

Cited by 18 publications

References 38 publications

Degeneration of Axotomized Projection Neurons in the Rat dLGN: Temporal Progression of Events and Their Mitigation by a Single Administration of FGF2

Degeneration of Axotomized Projection Neurons in the Rat dLGN: Temporal Progression of Events and Their Mitigation by a Single Administration of FGF2

Alcohol-induced apoptosis of oligodendrocytes in the fetal macaque brain

Lactoferrin during lactation protects the immature hypoxic‐ischemic rat brain

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