Influence of autophagy genes on ion-channel-dependent neuronal degeneration in <i>Caenorhabditis elegans</i>

Tóth, Márton L.; Šimon, Peter; Kovács, Attila; Vellai, Tibor

doi:10.1242/jcs.03401

Cited by 76 publications

(83 citation statements)

References 39 publications

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“…14,15 We find that loss of UNC-51 function strongly suppresses necrotic cell death, initiated by diverse genetically encoded insults in the nematode (Figure 1a and b), consistent with previous observations. 10 We examined whether the apparent reduction of necrotic neuron number in animal populations carrying mutations in UNC-51 is the result of delay rather than suppression of cell death. Generally, necrotic cell death triggered by mec-4(d), peaks during the L1 larval stage of C. elegans, with much less cell corpses being observed thereafter.…”

Section: Resultsmentioning

confidence: 99%

Autophagy is required for necrotic cell death in Caenorhabditis elegans

2007

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Autophagy is the main process for bulk protein and organelle recycling in cells under extracellular or intracellular stress. Deregulation of autophagy has been associated with pathological conditions such as cancer, muscular disorders and neurodegeneration. Necrotic cell death underlies extensive neuronal loss in acute neurodegenerative episodes such as ischemic stroke. We find that excessive autophagosome formation is induced early during necrotic cell death in C. elegans. In addition, autophagy is required for necrotic cell death. Impairment of autophagy by genetic inactivation of autophagy genes or by pharmacological treatment suppresses necrosis. Autophagy synergizes with lysosomal catabolic mechanisms to facilitate cell death. Our findings demonstrate that autophagy contributes to cellular destruction during necrosis. Thus, interfering with the autophagic process may protect neurons against necrotic damage in humans.

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Section: Resultsmentioning

confidence: 99%

Autophagy is required for necrotic cell death in Caenorhabditis elegans

2007

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“…Inhibition of autophagy suppresses necrotic neurodegeneration, whilst over-induction of autophagy exacerbates necrotic cell death in C. elegans Toth et al, 2007). Interestingly, the mouse anti-apoptotic protein Bcl-2 binds Beclin-1 and inhibits autophagy, whereas the proapoptotic BH3-only proteins release Beclin-1 from Bcl-2, activating autophagy (Pattingre et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Autophagy and ageing: Insights from invertebrate model organisms

Lionaki

Markaki

Tavernarakis

2013

Ageing Research Reviews

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a b s t r a c tAgeing in diverse species ranging from yeast to humans is associated with the gradual, lifelong accumulation of molecular and cellular damage. Autophagy, a conserved lysosomal, self-destructive process involved in protein and organelle degradation, plays an essential role in both cellular and whole-animal homeostasis. Accumulating evidence now indicates that autophagic degradation declines with age and this gradual reduction of autophagy might have a causative role in the functional deterioration of biological systems during ageing. Indeed, loss of autophagy gene function significantly influences longevity. Moreover, genetic or pharmacological manipulations that extend lifespan in model organisms often activate autophagy. Interestingly, conserved signalling pathways and environmental factors that regulate ageing, such as the insulin/IGF-1 signalling pathway and oxidative stress response pathways converge on autophagy. In this article, we survey recent findings in invertebrates that contribute to advance our understanding of the molecular links between autophagy and the regulation of ageing. In addition, we consider related mechanisms in other organisms and discuss their similarities and idiosyncratic features in a comparative manner.

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“…Recent studies in C. elegans indicate a causative role of autophagy in necrotic cell death. 71,52 Impairment of autophagy by downregulation of the autophagy genes bec-1, unc-51 and lgg-1 or pharmacological treatment interfering with autophagy partially suppresses necrotic neuronal death induced by hyperactive MEC-4, DEG-1 and DEG-3 ion channels. In contrast, autophagy upregulation by knockdown of the negative autophagy regulator CeTOR or under nutrient deprivation promotes neuron necrosis.…”

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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Influence of autophagy genes on ion-channel-dependent neuronal degeneration in Caenorhabditis elegans

Cited by 76 publications

References 39 publications

Autophagy is required for necrotic cell death in Caenorhabditis elegans

Autophagy is required for necrotic cell death in Caenorhabditis elegans

Autophagy and ageing: Insights from invertebrate model organisms

Autophagy and cell death in model organisms

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