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Cell Cycle,
2007]
Classic studies in diverse organisms, including humans, have demonstrated that aging is accompanied by marked alterations in both general and specific protein synthesis. These early observations established a link between the aging process and the regulation of protein synthesis. However, two important questions remained. First, what are the molecular mechanisms underlying the changes in protein synthesis during aging? Second, are these changes simply a consequence of aging or do they actually have a causative role in senescent decline? We have recently shown that elimination of a specific isoform of the eukaryotic mRNA translation initiation factor 4E (eIF4E) that functions in somatic cells, reduces protein synthesis and extends lifespan in the nematode Caenorhabditis elegans. Depletion of eIF4E in the soma extends lifespan via a mechanism independent of the insulin/IGF pathway that modulates aging in diverse species. Our findings suggest that regulation of protein synthesis is an important determinant of longevity and provide a framework for elucidating the mechanisms by which the rate of protein synthesis influences the process of aging.
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Ann N Y Acad Sci,
2001]
Mechanosensory signaling, believed to be mediated by mechanically gated ion channels, constitutes the basis for the senses of touch and hearing, and contributes fundamentally to the development and homeostasis of all organisms. Despite this profound importance in biology, little is known of the molecular identities or functional requirements of mechanically gated ion channels. Genetic analyses of touch sensation and locomotion in Caenorhabditis elegans have implicated a new class of ion channels, the degenerins (DEG) in nematode mechanotransduction. Related fly and vertebrate proteins, the epithelial sodium channel (ENaC) family, have been implicated in several important processes, including transduction of mechanical stimuli, pain sensation, gametogenesis, sodium reabsorption, and blood pressure regulation. Still-to-be-discovered DEG/ENaC proteins may compose the core of the elusive human mechanotransducer.
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Cell Biochem Biophys,
2001]
One of the looming mysteries in signal transduction today is the question of how mechanical signals, such as pressure or mechanical force delivered to a cell, are interpreted to direct biological responses. All living organisms, and probably all cells, have the ability to sense and respond to mechanical stimuli. At the single-cell level, mechanical signaling underlies cell-volume control and specialized responses such as the prevention of poly-spermy in fertilization. At the level of the whole organism, mechanotransduction underlies processes as diverse as stretch-activated reflexes in vascular epithelium and smooth muscles; gravitaxis and turgor control in plants; tissue development and morphogenesis; and the senses of touch, hearing, and balance. Intense genetic, molecular, and electrophysiological studies in organisms ranging from nematodes to mammals have highlighted members of the recently discovered DEG/ENaC family of ion channels as strong candidates for the elusive metazoan mechanotransducer. Here, we discuss the evidence that links DEG/ENaC ion channels to mechanotransduction and review the function of Caenorhabditis elegans members of this family called degenerins and their role in mediating mechanosensitive behaviors in the worm.
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Biochim Biophys Acta,
2009]
Macroautophagy (or autophagy) is a catabolic process responsible for the degradation of long-lived proteins, molecules and organelles. Cellular stressors such as food limitation, space restriction, oxidative stress, temperature shifts, and accumulation of protein aggregates induce autophagy. Cellular material to be degraded is engulfed in autophagosomes, which fuse with the lysosome where material is degraded. Cellular components can then be recycled. Autophagy has been assigned pro-survival and pro-death functions. Here, we reviewed the roles of autophagy in cell growth and death, in ageing and longevity, as well as in neurodegeneration in the nematode Caenorhabditis elegans.
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Prog Mol Biol Transl Sci,
2020]
Nuclear recycling is essential for cell and organismal homeostasis. Nuclear architecture perturbations, such as nuclear loss or nuclear enlargement, have been observed in several pathological conditions. Apart from proteasomal components which reside in the nucleus, specific autophagic proteins also shuttle between the nucleus and the cytoplasm. Until recently, only the microautophagic degradation of nuclear components had been described. Recent studies, dissecting nuclear material recycling in organisms ranging from yeast to mammals, provide insight relevant to other forms of nucleophagy and the mediators involved. Nucleophagy has also been implicated in pathology. Lamins are degraded in cancer through direct interaction with LC3 in the nucleus. Similarly, in neurodegeneration, Golgi-associated nucleophagy is exacerbated. The physiological role of nucleophagy and its contribution to other pathologies remain to be elucidated. Here we discus recent findings that shed light into the molecular mechanisms and pathways that mediate the autophagic recycling of nuclear material.
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Genetica,
2009]
The nematode Caenorhabditis elegans is a widely appreciated, powerful platform in which to study important biological mechanisms related to human health. More than 65% of human disease genes have homologues in the C. elegans genome, and essential aspects of mammalian cell biology, neurobiology and development are faithfully recapitulated in this organism. The EU-funded NemaGENETAG project was initiated with the aim to develop cutting-edge tools and resources that will facilitate modelling of human pathologies in C. elegans, and advance our understanding of animal development and physiology. The main objective of the project involves the generation and evaluation of a large collection of transposon-tagged mutants. In the process of achieving this objective the NemaGENETAG consortium also endeavours to optimize and automate existing transposon-mediated mutagenesis methodologies based on the Mos1 transposable element, in addition to developing alternatives using other transposon systems. The final product of this initiative-a comprehensive collection of transposon-tagged alleles-together with the acquisition of efficient transposon-based tools for mutagenesis and transgenesis in C. elegans, should yield a wealth of information on gene function, immediately relevant to key biological processes and to pharmaceutical research and development.
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Nature Reviews Neuroscience,
2003]
When stressed beyond their tolerance, cells undergo necrosis, an acute, non-apoptotic form of cell death. Necrosis is crucial to the damage that injury and disease inflict on the nervous system. Recent discoveries have shed light onto the molecular requirements for necrosis, and provide new evidence that, as is the case for apoptosis, the mechanisms of necrotic cell death are conserved from nematodes to humans. But in contrast to apoptotic mechanisms, necrotic mechanisms did not evolve specifically to carry out necrosis. Instead, under extreme circumstances, normal cellular activities are destabilized with devastating consequences for the cell. Here, we review the mechanisms that are implicated in necrosis and discuss the events that transform them to catastrophic for cell
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Dev Dyn,
2010]
The simple nematode worm Caenorhabditis elegans has been instrumental in deciphering the molecular mechanisms underlying apoptosis. Beyond apoptosis, several paradigms of non-apoptotic cell death, either genetically or extrinsically triggered, have also been described in C. elegans. Remarkably, non-apoptotic cell death in worms and pathological cell death in humans share numerous key features and mechanistic aspects. Such commonalities suggest that similarly to apoptosis, non-apoptotic cell death mechanisms are also conserved, and render the worm a useful organism, in which to model and dissect human pathologies. Indeed, the genetic malleability and the sophisticated molecular tools available for C. elegans have contributed decisively to advance our understanding of non-apoptotic cell death. Here, we review the literature on the various types of non-apoptotic cell death in C. elegans and discuss the implications, relevant to pathological conditions in humans.
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Mech Ageing Dev,
2002]
Oxidative damage to cellular macromolecules has been postulated to be a major contributor to the ageing of diverse organisms. Oxidative damage can be limited by maintaining high anti-oxidant defenses and by clearing/repairing damage efficiently. Protein turnover is one of the main routes by which functional proteins are maintained and damaged proteins are removed. Protein turnover rates decline with age, which might contribute to the accumulation of damaged proteins in ageing cells. Interestingly, protein turnover rates are maintained at high levels in caloric restricted animals. Whether changes in protein turnover are a cause or a consequence of ageing is not clear, and this question has not been a focal point of modern ageing research. Here we survey work on protein turnover and ageing and suggest that powerful genetic models such as the nematode Caenorhabditis elegans are well suited for a thorough investigation of this long-standing question.
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Cells,
2021]
Autophagy is an evolutionarily conserved degradation process maintaining cell homeostasis. Induction of autophagy is triggered as a response to a broad range of cellular stress conditions, such as nutrient deprivation, protein aggregation, organelle damage and pathogen invasion. Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane organelle referred to as the autophagosome with subsequent degradation of its contents upon delivery to lysosomes. Autophagy plays critical roles in development, maintenance and survival of distinct cell populations including neurons. Consequently, age-dependent decline in autophagy predisposes animals for age-related diseases including neurodegeneration and compromises healthspan and longevity. In this review, we summarize recent advances in our understanding of the role of neuronal autophagy in ageing, focusing on studies in the nematode <i>Caenorhabditis elegans</i>.