Bcl2a1 serves as a switch in death of motor neurons in amyotrophic lateral sclerosis

Crosio, Claudia; Casciati, Arianna; Iaccarino, Ciro; Rotilio, Giuseppe; Carrı̀, Maria Teresa

doi:10.1038/sj.cdd.4401943

Cited by 17 publications

(7 citation statements)

References 17 publications

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“…However, several reports challenge this statement, demonstrating that A1ΔCould be anti-apoptotic, or proapoptotic, depending on cell type and apoptotic stimulus [26–28]. In a microvascular endothelial cell line, A1 predominantly localized at the mitochondrial membrane, where it functioned to inhibit Cytochrome c release and Caspase 9 activation, maintaining mitochondrial transmembrane potential and promoting temporary survival of these cells in response to TNF [22].…”

Section: Resultsmentioning

confidence: 99%

“…This result is important because the cytoprotective effect of A1 is far from ubiquitous. Indeed, while A1 maintains its anti-apoptotic function in skeletal and cardiac myocytes and in several cancer cells [36–38], it promotes TNF-induced apoptosis of spinal cord motor neurons [28], B cells [26] and even 293T cells [27]. Surprisingly “anti-inflammatory” A1ΔC equally protected EC from cell death, proving that mitochondrial localization is not required for the pro-survival function of A1 in EC.…”

Section: Discussionmentioning

confidence: 99%

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The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cells

Guedes

Rocha

Mahiou

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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A1/Bfl-1 is a NF-κB dependent, anti-apoptotic Bcl-2 family member that contains four Bcl-2 homology domains (BH) and an amphipathic C-terminal domain, and is expressed in endothelial cells (EC). Based on NF-κB reporter assays in bovine aortic EC, we have previously demonstrated that A1, like Bcl-2 and Bcl-xL, inhibits NF-κB activation. These results, however, do not fully translate when evaluating the cell’s own NF-κB machinery in human EC overexpressing A1 by means of recombinant adenovirus (rAd.) mediated gene transfer. Indeed, overexpression of full-length A1 in human umbilical vein EC (HUVEC), and human dermal microvascular EC (HDMEC) failed to inhibit NF-κB activation. However, overexpression of a mutant lacking the C-terminal domain of A1 (A1ΔC) demonstrated a potent NF-κB inhibitory effect in these cells. Disparate effects of A1 and A1ΔC on NF-κB inhibition in human EC correlated with mitochondrial (A1) versus non-mitochondrial (A1ΔC) localization. In contrast, both full-length A1 and A1ΔC protected EC from staurosporine (STS)-induced cell death, indicating that mitochondrial localization was not necessary for A1’s cytoprotective function in human EC. In conclusion, our data uncover a regulatory role for the C-terminal domain of A1 in human EC: anchoring A1 to the mitochondrion, which conserves but is not necessary for its cytoprotective function, or by its absence freeing A1 from the mitochondrion and uncovering an additional anti-inflammatory effect.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cells

Guedes

Rocha

Mahiou

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…One possibility involves aberrant interactions of mutant SOD1 with mitochondrial proteins, resulting in disruption of their normal folding or import (29, 67). Thus, it was reported that mutant SOD1 interacts with proteins that may affect mitochondria directly or indirectly, including Hsps (78), members of the Bcl-2 family (22, 79), and components of the protein translation machinery (55, 59). We and others demonstrated that in yeast (96, 107), rats (78), and in transgenic mice expressing WT or mutant human SOD1 (44, 49, 67, 70, 79, 104), a substantial amount of SOD1, estimated at between 1 and 2% of total SOD1, is localized in various mitochondria compartments.…”

Section: Potential Mechanisms Of Mutant Sod1 Interference With Mitochmentioning

confidence: 99%

Mitochondrial Function, Morphology, and Axonal Transport in Amyotrophic Lateral Sclerosis

Magrané

Manfredi

2009

Antioxidants & Redox Signaling

110

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Perturbation of organellar axonal transport is increasingly recognized as an important contributor in a number of neurodegenerative diseases. Although the specificity of this impairment remains to be elucidated, growing evidence suggests that in certain disease conditions, mitochondria are affected primarily by transport defects. Many hypotheses have been formulated to explain the pathogenic mechanisms involved in amyotrophic lateral sclerosis (ALS). The mutations described so far in genetic forms of ALS (familial ALS, fALS) affect proteins involved in a wide variety of cellular mechanisms, including free radical scavenging, energy metabolism, axonal transport, RNA processing, DNA repair, vesicular transport, and angiogenesis. Here we review the current knowledge on mitochondrial transport and its role in ALS.

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“…To mimic an aspect of chronic neuroinflammation we infused TNF-α continuously for 14 days into the lateral ventricle of the mouse brain (Figure 2A) [24]. At 11 days after the start of the TNF-α infusion, the animals received an injection of the uridine analogue EdU to label proliferating cells.…”

Section: Resultsmentioning

confidence: 99%

Anti-inflammatory treatment induced regenerative oligodendrogenesis in parkinsonian mice

et al. 2012

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IntroductionThe adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how chronic neuroinflammation, as it occurs in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, affects adult neurogenesis and, therefore, modulates the brain's potential for self-regeneration.MethodsNeural stem cell culture techniques, intraventricular tumor necrosis factor (TNF)-α infusion and the 6-hydroxydopamine mouse model were used to investigate the influence of neuroinflammation on adult neurogenesis in the Parkinson's disease background. Microscopic methods and behavioral tests were used to analyze samples.ResultsHere, we demonstrate that differences in the chronicity of TNF-α application to cultured NSCs result in opposed effects on their proliferation. However, chronic TNF-α treatment, mimicking Parkinson's disease associated neuroinflammation, shows detrimental effects on neural progenitor cell activity. Inversely, pharmacological inhibition of neuroinflammation in a 6-hydroxydopamine mouse model led to increased neural progenitor cell proliferation in the subventricular zone and neuroblast migration into the lesioned striatum. Four months after surgery, we measured improved Parkinson's disease-associated behavior, which was correlated with long-term anti-inflammatory treatment. But surprisingly, instead of newly generated striatal neurons, oligodendrogenesis in the striatum of treated mice was enhanced.ConclusionsWe conclude that anti-inflammatory treatment, in a 6-hydroxydopamine mouse model for Parkinson's disease, leads to activation of adult neural stem cells. These adult neural stem cells generate striatal oligodendrocytes. The higher numbers of newborn oligodendrocytes possibly contribute to axonal stability and function in this mouse model of Parkinson's disease and thereby attenuate dysfunctions of basalganglian motor-control.

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Bcl2a1 serves as a switch in death of motor neurons in amyotrophic lateral sclerosis

Cited by 17 publications

References 17 publications

The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cells

The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cells

Mitochondrial Function, Morphology, and Axonal Transport in Amyotrophic Lateral Sclerosis

Anti-inflammatory treatment induced regenerative oligodendrogenesis in parkinsonian mice

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