Neuronal gelsolin prevents apoptosis by enhancing actin depolymerization

Harms, Christoph; Bösel, Julian; Lautenschlager, Marion; Harms, Ulrike; Braun, Johann; Hörtnagl, Heide; Dirnagl, Ulrich; Kwiatkowski, David J.; Fink, Klaus; Endres, Matthias

doi:10.1016/j.mcn.2003.09.012

Cited by 74 publications

(84 citation statements)

References 44 publications

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“…In our study, we also saw an increased activation of caspase-3 after knockdown of gelsolin by siRNA. This result is again consistent with a study showing that gsn Ϫ/Ϫ neurons are more susceptible to apoptosis after treatment with AF64A with an increase in the activation of caspase-3 (20).…”

Section: Discussionsupporting

confidence: 93%

“…In our case, further studies will be required to identify the pathway by which gelsolin protects pancreatic ␤-cells against apoptosis. This could possibly involve the remodeling of the actin cytoskeleton (20) or a direct inhibition of caspase-3 (15).…”

Section: Discussionmentioning

confidence: 99%

“…Gelsolin has thus been shown to block a target upstream of caspase-3 (14), to inhibit activation of caspase-3 by forming a complex with phosphatidylinositol 4,5-bisphosphate (15), to block loss of mitochondrial membrane potential and inhibit the release of cytochrome c (16,17), and to bind to and block the mitochondrial voltage-dependent anion channel (VDAC) (18). Furthermore, the anti-apoptotic role of gelsolin has been demonstrated both in vitro (19,20) and in vivo (21) by using gelsolin-null mice models.…”

mentioning

confidence: 99%

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Pro-Survival Role of Gelsolin in Mouse β-Cells

Yermen¹,

Tomás²,

Halban³

2007

Diabetes

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We have previously shown that the Ca 2؉ -dependent actinsevering protein gelsolin plays an important role in regulated insulin secretion. The aim of this study was to determine the role of gelsolin in ␤-cell survival as it has been shown to play a dual role in apoptosis in other cell types. MIN6 subclones B1 and C3, shown previously to express gelsolin at different levels (B1Ͼ ϾC3 cells), were used for this purpose. We demonstrate that B1 cells have lower levels of apoptosis and active caspase-3 when compared with C3 cells, in both standard (25 mmol/l glucose and 15% FCS) and deprived (5 mmol/l glucose and 1% FCS) conditions. Overexpression of gelsolin resulted in a decrease in the percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pro-Survival Role of Gelsolin in Mouse β-Cells

Yermen¹,

Tomás²,

Halban³

2007

Diabetes

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“…It has been reported that an intact cytoskeleton mediated by Rho/ROCK is necessary for overall ERK1/2 activation and their nuclear translocation, as well as activation of transcription in SDF-1-stimulated cells (Zhao et al, 2006), while disruption of actin cytoskeleton can induce apoptosis mediated by Bcl-2 in MEK-transformed EpH4 and MCF10A mammary epithelial cells (Martin and Leder, 2001;Pinkas et al, 2004). On the contrary, stabilization of actin cytoskeleton by downregulation of the actin severing protein, gelsolin (Harms et al, 2004) or by addition of jasplakinolide that induces large F-actin aggregates can also lead to increased apoptosis (Posey and Bierer, 1999). These data suggest that alterations in actin dynamics, either disruption or stabilization of actin cytoskeleton, could result in apoptosis.…”

Section: Discussionmentioning

confidence: 99%

RhoA prevents apoptosis during zebrafish embryogenesis through activation of Mek/Erk pathway

et al. 2007

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RhoA small GTPase, as a key regulator for actin cytoskeletal rearrangement, plays pivotal roles during morphogenesis, cytokinesis, phagocytosis and cell migration, but little is known about its signaling mechanism that controls cell survival in vivo. Using zebrafish as a model, we show that non-overlapping antisense morpholinos that block either translation or splicing of rhoA lead to extensive apoptosis during embryogenesis, resulting in overall reduction of body size and body length. These defects are associated with reduced activation of growth-promoting Erk and decreased expression of anti-apoptotic bcl-2. Moreover, ectopic expression of rhoA, Mek or BCL-2 mRNA rescues such phenotypes. Consistently, combined suppression of RhoA and Mek/Erk or Bcl-2 pathways by sub-optimal dose of rhoA morpholino and pharmacological inhibitors for either Mek (U0126) or Bcl-2 (HA 14-1) can induce developmental abnormalities and enhanced apoptosis, similar to those caused by effective RhoA knockdown. Furthermore, U0126 abrogates the rescue by RhoA and MEK but not BCL-2. In contrast, HA 14-1 effectively abolishes all functional rescues by RhoA, MEK or BCL-2, supporting that RhoA prevents apoptosis by activation of Mek/Erk pathway and requiring Bcl-2. These findings reveal an important genetic and functional relationship between RhoA with Mek/Erk and Bcl-2 for cell survival control during embryogenesis.

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“…So far, histological analyses of the brain of Gsn Ϫ/Ϫ mice have yielded no gross or microscopic anatomic abnormalities (Endres et al, 1999). We have previously demonstrated antiapoptotic and neuroprotective effects of gelsolin, which can also be harnessed pharmacologically (e.g., by inhibition of histone deacetylation) (Endres et al, 1999;Harms et al, 2004;Meisel et al, 2006;Yildirim et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Impact of Actin Filament Stabilization on Adult Hippocampal and Olfactory Bulb Neurogenesis

Kronenberg¹,

Gertz²,

Baldinger³

et al. 2010

J. Neurosci.

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Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca 2ϩ -activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn Ϫ/Ϫ ) mice as a model system for actin filament stabilization. In Gsn Ϫ/Ϫ mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca 2ϩ ] i increases and exocytotic neurotransmitter release were enhanced in Gsn Ϫ/Ϫ synaptosomes. Importantly, treatment of Gsn Ϫ/Ϫ synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca 2ϩ influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn Ϫ/Ϫ brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn Ϫ/Ϫ mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca 2ϩ influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn Ϫ/Ϫ hippocampus is associated with a special vascular niche for neurogenesis.

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Neuronal gelsolin prevents apoptosis by enhancing actin depolymerization

Cited by 74 publications

References 44 publications

Pro-Survival Role of Gelsolin in Mouse β-Cells

Pro-Survival Role of Gelsolin in Mouse β-Cells

RhoA prevents apoptosis during zebrafish embryogenesis through activation of Mek/Erk pathway

Impact of Actin Filament Stabilization on Adult Hippocampal and Olfactory Bulb Neurogenesis

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