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

Acarín, Laia; Villapol, Sonia; Faiz, Maryam; Rohn, Troy T.; Castellano, Bernardo; González, Berta

doi:10.1002/glia.20518

Cited by 81 publications

(111 citation statements)

References 61 publications

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“…Caspase-3 contributes to remodeling of the cytoskeleton as a protease in a non-apoptotic context in activated astrocytes by contributing to the reorganization of the cytoskeleton by means of vimentin cleavage (46). Caspase-3 is also implicated in the remodeling of the spectrin membrane skeleton during lens development and aging (47).…”

Section: Discussionmentioning

confidence: 99%

Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth

Westphal

Sytnyk

Schachner

et al. 2010

Journal of Biological Chemistry

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Changes in neuronal morphology underlying neuronal differentiation depend on rapid and sustained cytoskeleton rearrangements in the growing neurites. Whereas cell adhesion molecules are well established as regulators of neuronal differentiation, less is known about the signaling mechanisms by which they influence the cytoskeleton. Here we show that the neural cell adhesion molecule (NCAM) associates with the active form of caspase-8 and that clustering of NCAM at the neuronal cell surface leads to activation of caspase-8 and -3 followed by the cleavage of the sub-membranous brain spectrin meshwork, but not of the actin or tubulin cytoskeleton. Inhibitors of caspase-8 and -3 specifically block the NCAM-dependent spectrin cleavage and abolish NCAM-dependent neurite outgrowth. NCAM-dependent rearrangements of the membrane associated spectrin meshwork via caspase-8 dependent caspase-3 activation are thus indispensable for NCAM-mediated neurite outgrowth.The establishment and maintenance of neuronal morphology are essential for brain development and functioning. The neural cell adhesion molecule (NCAM) 2 plays a prominent role in these processes by being involved in regulation of neuronal migration and differentiation as well as synaptogenesis in the developing nervous system and synaptic plasticity in the adult (1-4). NCAM is a member of the immunoglobulin superfamily of adhesion molecules and contains five immunoglobulin and two fibronectin-like type III domains within its extracellular part. In developing neurons, NCAM is highly expressed in two transmembrane isoforms with molecular weights of 140 kDa (NCAM140) and, to a lower extent, 180 kDa (NCAM180), which are generated via alternative splicing of the ncam1 gene. The extracellular portion of NCAM interacts with multiple binding partners on adjacent cells and in the extracellular matrix, including adhesion molecules, such as prion protein (PrP), L1, and NCAM itself (5, 6), growth factor receptors, such as FGFR and GFR␣ (7,8), and other receptors, such as receptor-type protein phosphatase ␤ or its secreted forms (9).Clustering of NCAM at the cell surface by its ligands promotes neurite outgrowth by inducing intracellular signaling cascades, initiated by the association of the intracellular domain of NCAM with and consequent activation of kinases and phosphatases, including CaMKII␣, PKC, and RPTP␣ (10 -12). Palmitoylation of the intracellular domain of NCAM (13) and association of NCAM with the cellular form of prion protein (PrP) (5) promote redistribution of NCAM and associated signaling molecules to lipid rafts where they activate downstream signal transducing proteins including fyn kinase and GAP43 (10,12,14,15).The cytoskeleton plays an important role in NCAM-dependent signaling, and clustering of NCAM at the cell surface induces formation of the spectrin-based cytoskeleton enriched in microdomains (3). However, little is known on how NCAM signaling is coordinated with the cytoskeleton reorganization including not only its polymerization but also local remode...

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Section: Discussionmentioning

confidence: 99%

Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth

Westphal

Sytnyk

Schachner

et al. 2010

Journal of Biological Chemistry

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“…Caspase-3 has recently been suggested to be involved in functions besides apoptosis (e.g., cytoskeleton remodeling or synaptic pruning). For example, caspase-3 activation has been shown to be important for astroglial cytoskeleton remodeling after excitotoxic damage (37). It could not be excluded that the reducing effect of rhGH on the caspase-3 activity may include these actions.…”

Section: Discussionmentioning

confidence: 99%

Reversal of opiate-induced apoptosis by human recombinant growth hormone in murine foetus primary hippocampal neuronal cell cultures

Svensson

Bucht

Hallberg

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Previous studies have shown that chronic opiates may inhibit cell growth and trigger apoptosis leading to impaired cognitive capabilities in both humans and other mammals. In contrast, growth hormone (GH) has been demonstrated to stimulate cell growth and counteract apoptosis. GH has also been shown to improve learning and memory in both human and rodents. In this work, we demonstrate that GH may reverse opiate-induced apoptosis in cells derived from prenatal mouse hippocampus. Primary hippocampal cell cultures derived from 16-day-old fetal mouse neurons were treated with morphine for 7 days during growth in the absence or presence of recombinant human GH (rhGH). The release of lactate dehydrogenase (LDH) into the culture media and the level of cleaved caspase-3 were measured. Results indicate that morphine (15 M) decreased the cell content in a concentration-dependent manner and increased LDH release and caspase-3 activity. Thus, fetal mouse neurons treated with morphine showed less viability compared with controls. Interestingly, the addition of rhGH (1 M) counteracted the morphine-induced effect on the cell density. Furthermore, the hormone attenuated the effects on LHD release and caspase-3 activity elicited by morphine. These results suggest that the hormone is capable of preventing or even repairing morphine-induced damage to hippocampal cells.apoptosis ͉ morphine ͉ caspase-3 ͉ lactate dehydrogenase

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“…Berta Gonzalez from a well-characterized in vivo model of excitotoxicity in postnatal rats. 42 Protein extraction and western blot. Rats were anesthetised and decapitated at 3, 5, 7, and 9 days for sample preparation (n ¼ 3 per time point).…”

Section: Methodsmentioning

confidence: 99%

Autophagy, and BiP level decrease are early key events in retrograde degeneration of motoneurons

et al. 2011

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Disconnection of the axon from the soma of spinal motoneurons (MNs) leads either to a retrograde degenerative process or to a regenerative reaction, depending on the severity and the proximity to the soma of the axonal lesion. The endoplasmic reticulum (ER) is a continuous membranous network that extends from the nucleus to the entire cytoplasm of the neuronal soma, axon and dendrites. We investigated whether axonal injury is sensed by the ER and triggers the activation of protective mechanisms, such as the unfolded protein response (UPR) and autophagy. We found early (at 3 days) accumulation of beclin1, LC3II and Lamp-1, hallmarks of autophagy, in both degenerating MNs after spinal root avulsion and in non-degenerating MNs after distal nerve section, although Lamp-1 disappeared by 5 days only in the former. In contrast, only degenerating MNs presented early activation of IRE1a, revealed by an increase of the spliced isoform of Xbp1 and accumulation of ATF4 in their nucleus, two branches of the UPR, and late BiP downregulation in association with cytoskeletal and organelle disorganization. We conclude that BiP decrease is a signature of the degenerating process, as its overexpression led to an increase in MN survival after root avulsion. Besides, Bcl2 is strongly implicated in the survival pathway activated by BiP overexpression.

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

Cited by 81 publications

References 61 publications

Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth

Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth

Reversal of opiate-induced apoptosis by human recombinant growth hormone in murine foetus primary hippocampal neuronal cell cultures

Autophagy, and BiP level decrease are early key events in retrograde degeneration of motoneurons

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