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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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Neurosci Lett,
2017]
Proteinopathies constitute a diverse group of devastating neurodegenerative disorders, characterized by aberrant aggregation of specific proteins within neurons and in the brain parenchyma. Parkinson's disease (PD) is among the most common proteinopathies, caused by the accumulation of different species of -synuclein and the formation of protein inclusions known as Lewy bodies. Although several mutations in the -synuclein gene have been linked to PD, the mechanisms mediating the aggregation and toxicity of -synuclein are not fully understood. Here, we review recent evidence that highlight an intricate interplay between -synuclein and ionostasis, focusing on the PMR1 pump, a Golgi resident Ca(2+)/Mn(2+) P-type ATPase, which plays a pivotal role in regulating the intracellular levels of calcium and manganese ions.
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Mech Ageing Dev,
2005]
The ageing process precipitates dramatic alterations in the physiology of all organisms, including reduced cellular function, compromised resistance to stress and pathological agents, and increased likelihood of developing age-related diseases. Among the, most characteristic pathologies associated with old age are numerous late-onset neurodegenerative disorders such as Alzheimer's. Parkinson's and Huntington's diseases. In addition to stroke, which also inflicts loss of neuronal cells, these conditions account for ever-increasing debilitation among the elderly. Recent studies in model organisms such as the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. which offer the prowess of sophisticated genetic approaches. have uncovered significant, novel aspects of the molecular mechanisms that underlie both neurodegeneration and the ageing process. These advances hold promise that the intimate link between the, aged state and the manifestation of several neurodegenerative diseases will be deciphered. Here. we discuss the mechanisms by which ageing interfaces with. and influences, the progression of neurodegeneration.
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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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Curr Opin Biotechnol,
2020]
The nematode Caenorhabditis elegans offers unique advantages that enable a comprehensive delineation of the cellular and molecular mechanisms underlying devastating human pathologies such as stroke, ischemia and age-associated neurodegenerative disorders. Genetic models of human diseases that closely simulate several disease-related phenotypes have been established in the worm. These models allow the implementation of multidisciplinary approaches, in addition to large-scale genetic and pharmacological screenings, designed to elucidate the molecular mechanisms mediating pathogenesis and to identify targets and drugs for emergent therapeutic interventions. Such strategies have already provided valuable insights, highly relevant to human health and quality of life. This article considers the potential of C. elegans as a versatile platform for systematic dissection of the molecular basis of human disease, focusing on neurodegenerative disorders.
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Ageing Res Rev,
2003]
Proteolytic mechanisms have been implicated in the process of ageing, and in many neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, which are most prevalent in old age. Simple model organisms such as the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, which offer the prowess of sophisticated genetic approaches, have contributed to our understanding of ageing and neurodegeneration. Intensive research in these systems has resulted in detailed models of the ageing process, and also of several neurodegenerative diseases, which recapitulate same aspects of the human pathologies. Inappropriate cell death is a major component of these and other devastating conditions such as stroke. The dissection of the molecular mechanisms underlying the process of cell degeneration in ageing is of utmost importance. Evidence from investigations in C. elegans implicates deregulated proteolysis as one major determinant of cellular destruction in neurodegeneration and ageing, and suggests that the process depends critically on the activation of calcium-dependent, calpain proteases and lysosomal aspartyl proteases. Apart from shedding light on important but inadequately understood facets of such phenomena, these discoveries hold promise for developing novel, effective intervention strategies aiming to ameliorate or even counter inappropriate cell