Closed Head Injury Induces Upregulation of Beclin 1 at the Cortical Site of Injury

Diskin, Tal; Tal-Or, Pazit; Erlich, Shlomit; Mizrachy, Liat; Alexandrovich, Alexander; Shohami, Esther; Pinkas‐Kramarski, Ronit

doi:10.1089/neu.2005.22.750

Cited by 164 publications

(151 citation statements)

References 24 publications

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“…An LC3 shift has been reported in mice of various ages after unilateral carotid artery ligation and hypoxemia (Adhami et al, 2006;Zhu et al, 2003). After closed head injury, upregulation of Beclin-1 has been reported within neurons in injured hippocampus and cortex in mice (Diskin et al, 2005). Our data provide direct ultrastructural evidence of autophagy after acute brain injury (Figures 1 and 2) in addition to biochemical alterations in LC3.…”

Section: Discussionsupporting

confidence: 72%

Autophagy is Increased after Traumatic Brain Injury in Mice and is Partially Inhibited by the Antioxidant γ-glutamylcysteinyl Ethyl Ester

Lai

Chen

et al. 2007

J Cereb Blood Flow Metab

160

112

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Autophagy is a homeostatic process for recycling of proteins and organelles, induced by nutrient deprivation and regulated by oxygen radicals. Whether autophagy is induced after traumatic brain injury (TBI) is not established. We show that TBI in mice results in increased ultrastructural and biochemical evidence of autophagy. Specifically, autophagosomal vacuoles and secondary lysosomes were frequently observed in cell processes and axons in ipsilateral brain regions by electron microscopy, and lipidated microtubule-associated protein light chain 3, a biochemical footprint of autophagy referred to as LC3 II, was increased at 2 and 24 h after TBI versus controls. Since oxygen radicals are believed to be important in the pathogenesis of TBI and are essential for the process of starvation-induced autophagy in vitro, we also sought to determine if treatment with the antioxidant c-glutamylcysteinyl ethyl ester (GCEE) reduced autophagy and influenced neurologic outcome after TBI in mice. Treatment with GCEE reduced oxidative stress and partially reduced LC3 II formation in injured brain at 24 h after TBI versus vehicle. Treatment with GCEE also led to partial improvement in behavioral and histologic outcome versus vehicle. Taken together, these data show that autophagy occurs after experimental TBI, and that oxidative stress contributes to overall neuropathology, in part by initiating or influencing autophagy.

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Section: Discussionsupporting

confidence: 72%

Autophagy is Increased after Traumatic Brain Injury in Mice and is Partially Inhibited by the Antioxidant γ-glutamylcysteinyl Ethyl Ester

Lai

Chen

et al. 2007

J Cereb Blood Flow Metab

160

112

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“…Traumatic brain injury in mice leads to elevation of Beclin-1 levels in neurons and in astrocytes. 62 unilateral common carotid artery occlusion display cytoplasmic vacuolization, lysis of intracellular organelles and activated autophagy. 64 In addition, autophagy upregulation occurs in murine and chicken models of excitotoxicity.…”

Section: Autophagy-necrosis Interplaymentioning

confidence: 99%

Autophagy and cell death in model organisms

2008

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Autophagy evolved in unicellular eukaryotes as a means for surviving nutrient stress. During the course of evolution, as multicellular organisms developed specialized cell types and complex intracellular signalling networks, autophagy has been summoned to serve additional cellular functions. Numerous recent studies indicate that apart from its pro-survival role under nutrient limitation, autophagy also participates in cell death. However, the precise role of this catabolic process in dying cells is not fully understood. Although in certain situations autophagy has a protective function, in other types of cell death it actually contributes to cellular destruction. Simple model organisms ranging from the unicellular Saccharomyces cerevisiae to the soil amoeba Dictyostelium discoideum and the metazoans Caenorhabditis elegans and Drosophila melanogaster provide clearly defined cell death paradigms that can be used to dissect the involvement of autophagy in cell death, at the molecular level. In this review, we survey current research in simple organisms, linking autophagy to cell death and discuss the complex interplay between autophagy, cell survival and cell death. Autophagy is a self-degradation process that is essential for survival, differentiation, development, and homeostasis. There are at least three forms of autophagy -chaperonemediated autophagy, microautophagy, and macroautophagy -that differ with respect to their mechanisms, physiological functions and cargo specificity. In the best-studied form of autophagy, macroautophagy (herein referred to as autophagy), parts of the cytoplasm, long-lived proteins and intracellular organelles are sequestered within cytoplasmic double-membrane vesicles called autophagosomes or autophagic vacuoles. These characteristic vacuoles are finally delivered to lysosomes for bulk degradation (Figure 1).Autophagy was discovered in mammalian cells and has been extensively investigated in yeast. 1 These studies have identified many genes encoding proteins involved in autophagy (ATG proteins). 2 ATG proteins participate in the induction of autophagy, the formation, expansion and maturation of autophagosomes, and in the retrieval of autophagic proteins from mature autophagosomes. 3 Fusion processes occur through the t-and v-SNARE complexes, and other molecules, such as the Rab GTPases and components of the vacuolar protein-sorting (VPS) complex. Several protein kinases regulate autophagy, the best characterized being the mammalian target of rapamycin (mTOR), which negatively regulates the pathway. 4 Downstream of TOR kinase, numerous proteins encoded by ATG genes (more than 20 genes in yeast) are essential for the execution of autophagy. 5 The autophagic process is evolutionarily conserved and most yeast ATG genes have homologues in higher organisms (Table 1).Autophagy has also been linked to cell death pathways. Indeed, excess cytoplasmic vacuolation is the main feature of type II programmed cell death or autophagic cell death. Both protective and destructive contributions of autop...

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“…Autophagy plays a key role in cell homeostasis and is a central mechanism for adaptation to starvation immediately after birth and in normal growth control, 1 but also represents a strategy by which cells survive bioenergetic stress. Autophagy is also rapidly activated in neurons exposed to hypoxic 2 or excitotoxic stimuli, 3 as well as after closed head injury 4 or focal cerebral ischemia. 5 Although considered primarily a homeostatic response, the presence of autophagic structures in dying cells has implicated autophagy in the cell death process, as excessive autophagic activity may destroy proportions of the cytosol and organelles, leading to the total collapse of all cellular functions.…”

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confidence: 99%