Non-lethal active caspase-3 expression in Bergmann glia of postnatal rat cerebellum

Oomman, Sowmini; Strahlendorf, Howard K.; Finckbone, VelvetLee; Strahlendorf, Jean C.

doi:10.1016/j.devbrainres.2005.07.010

Cited by 39 publications

(39 citation statements)

References 73 publications

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“…The nuclear localization of cleaved caspase-3 in astrocytes has not only been previously demonstrated in injury paradigms (Acarin et al, 2005;Benjelloun et al, 2003;Johnson et al, 2005), but also in astrocytes of the normal adult CNS (Noyan-Ashraf et al, 2005) and in differentiating Bergmann glial cells (Oomman et al, 2005). It is largely established that during apoptosis, caspase-3 is the main protease responsible for the cleavage of nuclear proteins, like Poly(ADP-ribose) Polymerase-1 (PARP-1), acinus, and lamins (Eldadah and Faden, 2000), inducing DNA damage and chromatin condensation.…”

Section: Cleaved Caspase-3 Is Found In the Astroglial Nucleimentioning

confidence: 72%

“…Although the preponderance of data has emerged from work in the immune system and peripheral organs, several studies have also suggested non-apoptotic roles of caspase-3 in the CNS. Under physiological conditions, caspase-3 has been implicated in neuronal cytoskeletal changes (Rohn et al, 2004), in synaptic remodeling (Dash et al, 2000;Shimohama et al, 2001), in neuronal survival associated with preconditioning (Garnier et al 2003;McLaughlin et al, 2003;Tanaka et al, 2004), in the differentiation of cerebellar Bergmann glial cells (Oomman et al, 2004(Oomman et al, , 2005(Oomman et al, , 2006, and as a marker of astroglial subpopulations (Noyan-Ashraf et al, 2005). Accordingly, following excitotoxic damage in the neonatal brain we have demonstrated that presence of cleaved caspase-3 in nitrated reactive astrocytes in the absence of cell death (Acarin et al, 2005).…”

Section: Introductionmentioning

confidence: 79%

“…With regards to glial cell differentiation, Oomann and coworkers, who have described cleaved caspase-3 in Bergmann glia during postnatal development in the absence of apoptotic or proliferation markers, have demonstrated a role of this protease in differentiation processes (Oomman et al, 2004(Oomman et al, , 2005(Oomman et al, , 2006. In addition, it was recently shown that constitutive non-apoptotic expression of the cleaved form of caspase-3 occurs in the nuclei of a subpopulation of astrocytes in the cerebellar cortex, hippocampus, and spinal cord of adult rats of different strains, which show expression of the sodium dependent glutamate transporter (EAAT1, GLAST) (Noyan-Ashraf et al, 2005).…”

Section: Presence Of Caspase-cleaved Gfapmentioning

confidence: 99%

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Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

Acarín¹,

Villapol²,

Faiz³

et al. 2007

Glia

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Caspase-3 has classically been defined as the main executioner of programmed cell death. However, recent data supports the participation of this protease in non-apoptotic cellular events including cell proliferation, cell cycle regulation, and cellular differentiation. In this study, astroglial cleavage of caspase-3 was analyzed following excitotoxic damage in postnatal rats to determine if its presence is associated with apoptotic cell death, cell proliferation, or cytoskeletal remodeling. A well-characterized in vivo model of excitotoxicity was studied, where damage was induced by intracortical injection of N-methyl-D-asparate (NMDA) in postnatal day 9 rats. Our results demonstrate that cleaved caspase-3 was mainly observed in the nucleus of activated astrocytes in the lesioned hemisphere as early as 4 h postlesion and persisted until the glial scar was formed at 7-14 days, and it was not associated with TUNEL labeling. Caspase-3 enzymatic activity was detected at 10 h and 1 day postlesion in astrocytes, and co-localized with caspasecleaved fragments of glial fibrillary acidic protein (CCP-GFAP). However, at longer survival times, when astroglial hypertrophy was observed, astroglial caspase-3 did not generally correlate with GFAP cleavage, but instead was associated with de novo expression of vimentin. Moreover, astroglial caspase-3 cleavage was not associated with BrdU incorporation. These results provide further evidence for a nontraditional role of caspases in cellular function that is independent of cell death and suggest that caspase activation is important for astroglial cytoskeleton remodeling following cellular injury. V V C 2007 Wiley-Liss, Inc.

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Section: Cleaved Caspase-3 Is Found In the Astroglial Nucleimentioning

confidence: 72%

Section: Introductionmentioning

confidence: 79%

Section: Presence Of Caspase-cleaved Gfapmentioning

confidence: 99%

See 1 more Smart Citation

Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

Acarín¹,

Villapol²,

Faiz³

et al. 2007

Glia

View full text Add to dashboard Cite

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“…Actually, it is known that apoptosis has connections with cell differentiation (24). For instance, caspase-3 activation has been shown to be critically related to the differentiation of myoblasts (25), osteoclasts (26), bone marrow stromal cells (27), neurons (28), and neural and glial progenitor cells (29,30), suggesting the notion that the caspase apoptotic pathway regulates not only cell death but also cell differentiation. However, it is still a standing question what causes differentiation versus death phenotype, as caspases seem to target the same substrates in both processes.…”

Section: Discussionmentioning

confidence: 99%

NEU3 Sialidase Strictly Modulates GM3 Levels in Skeletal Myoblasts C2C12 Thus Favoring Their Differentiation and Protecting Them from Apoptosis

Anastasia

Papini

Colazzo

et al. 2008

Journal of Biological Chemistry

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Membrane-bound sialidase NEU3, often referred to as the "ganglioside sialidase," has a critical regulatory function on the sialoglycosphingolipid pattern of the cell membrane, with an anti-apoptotic function, especially in cancer cells. Although other sialidases have been shown to be involved in skeletal muscle differentiation, the role of NEU3 had yet to be disclosed. Herein we report that NEU3 plays a key role in skeletal muscle differentiation by strictly modulating the ganglioside content of adjacent cells, with special regard to GM3. Induced down-regulation of NEU3 in murine C2C12 myoblasts, even when partial, totally inhibits their capability to differentiate by increasing the GM3 level above a critical point, which causes epidermal growth factor receptor inhibition (and ultimately its down-regulation) and an higher responsiveness of myoblasts to the apoptotic stimuli.Skeletal muscle differentiation is a multistep process in which myoblasts, upon exit from the cell cycle, differentiate into myocytes and eventually fuse into multinucleated myotubes (1, 2). Muscle cell commitment to differentiation is strictly regulated by a group of transcription factors, referred to as the myogenic regulatory factors (3, 4). During differentiation, a profound remodeling of both cell plasma membrane and cytoskeleton takes place, which ultimately leads to the formation of multinucleated syncytia (myotubes) (5). These events have also been shown to be associated with modifications of the cell surface lipid composition, with a key role being played particularly by sialylated glycolipids (gangliosides) (6 -8). Along this line, sialidases (9), the enzymes that specifically remove sialic acid from sialylated glycoconjugates, have been shown to participate in the regulation of the myogenic event (10 -12). These findings further corroborate the evidence that sialidases, and their sialylated substrates, are fundamental in many physiological processes and that their de-regulation may lead to different pathologies, including cancer (13-16). Mammals possess four different sialidases (NEU1, NEU2, NEU3, NEU4) with different subcellular localization and substrate specificity, suggesting that each of them may possess a characteristic role. Actually, the cytosolic sialidase NEU2 and the lysosomal sialidase NEU1 seem to have different functions in skeletal muscle differentiation. In fact, the cytosolic sialidase gradually increases during muscle differentiation (10), and an induced down-regulation of the enzyme completely inhibits muscle differentiation, suggesting that NEU2 exerts its activity by desialylating key glycoconjugates involved in the process. On the other hand, lysosomal sialidase NEU1 shows an increase of both enzyme expression and activity only during the first stages of muscle differentiation, followed by their decrease, suggesting a possible regulatory role of NEU1 in the early stages of myogenesis (12). Moreover, the NEU1 promoter was proven to be highly up-regulated by MyoD and repressed by activated MEK 3 kinase, further ...

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“…3, A and B). Although caspases, and specifically caspase-3, have been implicated in a nonapoptotic role in the regulation of the cell cycle, cell proliferation, and cell differentiation (32,33), active caspase-3 is intimately linked to apoptotic events and is a key downstream effector in the execution of apoptosis. Neuron apoptosis is predominantly associated with high levels of caspase-3 activation following insult, although low levels of caspase-3 activation were found in astrocytes in the absence of cell death (34).…”

Section: -Week Ethanol Consumption Induces Neuronal Death In Thementioning

confidence: 99%

Alcohol-induced One-carbon Metabolism Impairment Promotes Dysfunction of DNA Base Excision Repair in Adult Brain

Fowler

Hewetson

Agrawal

et al. 2012

Journal of Biological Chemistry

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Background: DNA repair dysfunction leads to genomic instability and neuron death. Results: Long term alcohol exposure results in reduced DNA repair, increased DNA damage, and neuron death in adult brain. Conclusion: Long term alcohol exposure in adult brain promotes genomic instability mediated by impairment in one-carbon metabolism. Significance: This is the first demonstration of alcohol-induced genomic instability in brain.The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr ؉/؊ mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C3 T, common in human population, may exaggerate the adverse effects of ethanol on the brain.Nearly 100 million people worldwide have alcohol use disorders. Brain damage is a common and potentially severe consequence of alcohol abuse (1). It is estimated that 50 -75% of long term alcoholics exhibit cognitive impairment and structural damage to the brain. It is also known that chronic alcohol abuse is associated with cerebral cortical atrophy (1). Neuropathological analyses have provided evidence for loss of neurons in certain brain regions such as frontal lobes, which are highly affected in the alcoholic brain (1, 2). This region is essential for executive functions, whose loss may lead to a progressive loss of these functions, as seen in people addicted to alcohol as well as in individuals with frontal cortical damage (2, 3). These structural and cognitive changes have been suggested as the primary consequence of alcohol toxicity (4).Alcohol consumption is associated with generation of genotoxic metabolit...

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Non-lethal active caspase-3 expression in Bergmann glia of postnatal rat cerebellum

Cited by 39 publications

References 73 publications

Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

NEU3 Sialidase Strictly Modulates GM3 Levels in Skeletal Myoblasts C2C12 Thus Favoring Their Differentiation and Protecting Them from Apoptosis

Alcohol-induced One-carbon Metabolism Impairment Promotes Dysfunction of DNA Base Excision Repair in Adult Brain

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