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Nektarios Tavernarakis

Publications and source records attributed to Nektarios Tavernarakis.

18 recordsLinked to original sources
PubMed2006

Non-developmentally programmed cell death in Caenorhabditis elegans.

The simple nematode worm Caenorhabditis elegans has played a pivotal role in deciphering the molecular mechanisms of apoptosis. Precisely 131 somatic cells undergo programmed apoptotic death during development to contour the 959-cell adult organism. In addition to developmental cell death, specific genetic manipulations and extrinsic factors can trigger non-programmed cell death that is morphologically and mechanistically distinct from apoptosis. Here, we survey paradigms of cell death that is not developmentally programmed in C. elegans and review the molecular mechanisms involved. Furthermore, we consider the potential of the nematode as a platform to investigate pathological cell death. The striking extent of conservation between apoptotic pathways in worms and higher organisms including humans, holds promise that similarly, studies of non-programmed cell death in C. elegans will yield significant new insights, highly relevant to human pathology.

Animals↗
PubMed2006

Signaling pathways regulating protein synthesis during ageing.

Ageing in many organisms, including humans, is accompanied by marked alterations in both general and specific protein synthesis. Protein synthesis is normally under tight control by a broad array of regulatory factors, which facilitate appropriate rates of mRNA translation. Are the wide changes in protein synthesis simply a corollary of the ageing process or do they have a causative role in senescent decline? The jury is still out on this important question. Nevertheless, recent studies reveal an intimate interface between mechanisms that govern the translation of mRNA and molecular pathways implicated in ageing. In our manuscript we consider these links, which potentially underlie age-associated changes in protein synthesis.

Aging↗
PubMed2006

Lysosomal biogenesis and function is critical for necrotic cell death in Caenorhabditis elegans.

Necrotic cell death is defined by distinctive morphological characteristics that are displayed by dying cells (Walker, N.I., B.V. Harmon, G.C. Gobe, and J.F. Kerr. 1988. Methods Achiev. Exp. Pathol. 13:18-54). The cellular events that transpire during necrosis to generate these necrotic traits are poorly understood. Recent studies in the nematode Caenorhabditis elegans show that cytoplasmic acidification develops during necrosis and is required for cell death (Syntichaki, P., C. Samara, and N. Tavernarakis. 2005. Curr. Biol. 15:1249-1254). However, the origin of cytoplasmic acidification remains elusive. We show that the alkalization of endosomal and lysosomal compartments ameliorates necrotic cell death triggered by diverse stimuli. In addition, mutations in genes that result in altered lysosomal biogenesis and function markedly affect neuronal necrosis. We used a genetically encoded fluorescent marker to follow lysosome fate during neurodegeneration in vivo. Strikingly, we found that lysosomes fuse and localize exclusively around a swollen nucleus. In the advanced stages of cell death, the nucleus condenses and migrates toward the periphery of the cell, whereas green fluorescent protein-labeled lysosomal membranes fade, indicating lysosomal rupture. Our findings demonstrate a prominent role for lysosomes in cellular destruction during necrotic cell death, which is likely conserved in metazoans.

Animals↗
PubMed2006

The Genomes On Line Database (GOLD) v.2: a monitor of genome projects worldwide.

The Genomes On Line Database (GOLD) is a web resource for comprehensive access to information regarding complete and ongoing genome sequencing projects worldwide. The database currently incorporates information on over 1500 sequencing projects, of which 294 have been completed and the data deposited in the public databases. GOLD v.2 has been expanded to provide information related to organism properties such as phenotype, ecotype and disease. Furthermore, project relevance and availability information is now included. GOLD is available at http://www.genomesonline.org. It is also mirrored at the Institute of Molecular Biology and Biotechnology, Crete, Greece at http://gold.imbb.forth.gr/

Databases, Nucleic Acid↗
PubMed2006

Caenorhabditis elegans: a versatile platform for drug discovery.

Drug discovery and drug target identification are two intimately linked facets of intervention strategies aimed at effectively combating pathological conditions in humans. Simple model organisms provide attractive platforms for devising and streamlining efficient drug discovery and drug target identification methodologies. The nematode worm Caenorhabditis elegans has emerged as a particularly convenient and versatile tool that can be exploited to achieve these goals. Although C. elegans is a relatively modern addition to the arsenal of model organisms, its biology has already been investigated to an exceptional level. This, coupled with effortless handling and a notable low cost of cultivation and maintenance, allows seamless implementation of high-throughput drug screening approaches as well as in-depth genetic and biochemical studies of the molecular pathways targeted by specific drugs. In this review, we introduce C. elegans as a model organism with significant advantages toward the identification of molecular drug targets. In addition, we discuss the value of the worm in the development of drug screening and drug evaluation protocols. The unique features of C. elegans, which greatly facilitate drug studies, hold promise for both deciphering disease pathogenesis and formulating educated and effective therapeutic interventions.

Animals↗
PubMed2006

The role of synaptic ion channels in synaptic plasticity.

The nervous system receives a large amount of information about the environment through elaborate sensory routes. Processing and integration of these wide-ranging inputs often results in long-term behavioural alterations as a result of past experiences. These relatively permanent changes in behaviour are manifestations of the capacity of the nervous system for learning and memory. At the cellular level, synaptic plasticity is one of the mechanisms underlying this process. Repeated neural activity generates physiological changes in the nervous system that ultimately modulate neuronal communication through synaptic transmission. Recent studies implicate both presynaptic and postsynaptic ion channels in the process of synapse strength modulation. Here, we review the role of synaptic ion channels in learning and memory, and discuss the implications and significance of these findings towards deciphering the molecular biology of learning and memory.

Animals↗
PubMed2005

The vacuolar H+ -ATPase mediates intracellular acidification required for neurodegeneration in C. elegans.

Numerous studies implicate necrotic cell death in devastating human pathologies such as stroke and neurodegenerative diseases. Investigations in both nematodes and mammals converge to implicate specific calpain and aspartyl proteases in the execution of necrotic cell death. It is believed that these proteases become activated under conditions that inflict necrotic cell death. However, the factors that modulate necrosis and govern the erroneous activation of these otherwise benign enzymes are largely unknown. Here we show that the function of the vacuolar H(+)-ATPase, a pump that acidifies lysosomes and other intracellular organelles, is essential for necrotic cell death in C. elegans. Cytoplasmic pH drops in dying cells. Intracellular acidification requires the vacuolar H(+)-ATPase, whereas alkalization of endosomal and lysosomal compartments by weak bases protects against necrosis. In addition, we show that vacuolar H(+)-ATPase activity is required downstream of cytoplasmic calcium overload during necrosis. Thus, intracellular pH is an important modulator of necrosis in C. elegans. We propose that vacuolar H(+)-ATPase activity is required to establish necrosis-promoting, acidic intracellular conditions that augment the function of executioner aspartyl proteases in dying cells. Similar mechanisms may contribute to necrotic cell death that follows extreme acidosis-for example, during stroke-in humans.

Animals↗
PubMed2005

Proteolytic mechanisms in necrotic cell death and neurodegeneration.

Programmed neuronal cell death is required during development to achieve the accurate wiring of the nervous system. However, genetic or accidental factors can lead to the premature, non-programmed death of neurons during adult life. Inappropriate death of cells in the nervous system is the cause of multiple neurodegenerative disorders. Pathological neuronal death can occur by apoptosis, by necrosis or by a combination of both. Necrotic cell death underlies the pathology of devastating neurological diseases such as neurodegenerative disorders, stroke or trauma. However, little is known about the molecular mechanisms that bring about necrotic cell death. Proteases play crucial roles in neuron degeneration by exerting both regulatory and catabolic functions. Elevated intracellular calcium is the most ubiquitous feature of neuronal death with the concomitant activation of cysteine calcium-dependent proteases, calpains. Calpains and lysosomal, catabolic aspartyl proteases, play key roles in the necrotic death of neurons. In this review, we survey the recent literature on the role of cysteine and aspartyl proteases in necrosis and neurodegeneration, aiming to delineate common proteolytic mechanisms mediating cellular destruction.

Animals↗
PubMed2005

Neurodegenerative conditions associated with ageing: a molecular interplay?

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.

Aging↗
PubMed2004

Genetic models of mechanotransduction: the nematode Caenorhabditis elegans.

Mechanotransduction, the conversion of a mechanical stimulus into a biological response, constitutes the basis for a plethora of fundamental biological processes such as the senses of touch, balance, and hearing and contributes critically to development and homeostasis in all organisms. Despite this profound importance in biology, we know remarkably little about how mechanical input forces delivered to a cell are interpreted to an extensive repertoire of output physiological responses. Recent, elegant genetic and electrophysiological studies have shown that specialized macromolecular complexes, encompassing mechanically gated ion channels, play a central role in the transformation of mechanical forces into a cellular signal, which takes place in mechanosensory organs of diverse organisms. These complexes are highly efficient sensors, closely entangled with their surrounding environment. Such association appears essential for proper channel gating and provides proximity of the mechanosensory apparatus to the source of triggering mechanical energy. Genetic and molecular evidence collected in model organisms such as the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the mouse highlight two distinct classes of mechanically gated ion channels: the degenerin (DEG)/epithelial Na(+) channel (ENaC) family and the transient receptor potential (TRP) family of ion channels. In addition to the core channel proteins, several other potentially interacting molecules have in some cases been identified, which are likely parts of the mechanotransducing apparatus. Based on cumulative data, a model of the sensory mechanotransducer has emerged that encompasses our current understanding of the process and fulfills the structural requirements dictated by its dedicated function. It remains to be seen how general this model is and whether it will withstand the impiteous test of time.

Animals↗
PubMed2003

Calcium-dependent and aspartyl proteases in neurodegeneration and ageing in C. elegans.

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 death.

Aging↗
PubMed2002

Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans.

Necrotic cell death underlies the pathology of numerous human neurodegenerative conditions. In the nematode Caenorhabditis elegans, gain-of-function mutations in specific ion channel genes such as the degenerin genes deg-1 and mec-4, the acetylcholine receptor channel subunit gene deg-3 and the G(s) protein alpha-subunit gene gsa-1 evoke an analogous pattern of degenerative (necrotic-like) cell death in neurons that express the mutant proteins. An increase in concentrations of cytoplasmic calcium in dying cells, elicited either by extracellular calcium influx or by release of endoplasmic reticulum stores, is thought to comprise a major death-signalling event. But the biochemical mechanisms by which calcium triggers cellular demise remain largely unknown. Here we report that neuronal degeneration inflicted by various genetic lesions in C. elegans requires the activity of the calcium-regulated CLP-1 and TRA-3 calpain proteases and aspartyl proteases ASP-3 and ASP-4. Our findings show that two distinct classes of proteases are involved in necrotic cell death and suggest that perturbation of intracellular concentrations of calcium may initiate neuronal degeneration by deregulating proteolysis. Similar proteases may mediate necrotic cell death in humans.

Animals↗
PubMed2002

Induction of RNA interference in Caenorhabditis elegans by RNAs derived from plants exhibiting post-transcriptional gene silencing.

The term 'gene silencing' refers to transcriptional and post-transcriptional control of gene expression. Related processes are found across kingdoms in plants and animals. We intended to test whether particular RNA constituents of a silenced plant can induce silencing in an animal. We generated Nicotiana benthamiana lines that expressed green fluorescent protein (GFP) from a transgene. Plants in which GFP expression was spontaneously silenced showed siRNAs characteristic of post-transcriptional gene silencing (PTGS). RNA extracts prepared from silenced plants were injected into a GFP-expressing strain of Caenorhabditis elegans, where they induced RNA interference (RNAi). Extracts from non-silenced plants were inactive. This directly demonstrates a relationship and a mechanistic link between PTGS and RNAi. Controls confirmed that the silencing agent was an RNA. Size fractionation on denaturing gels revealed that an RNA of approximately 85 nt was most active in inducing silencing in the worm. Northern blot analysis of the region in question did not detect a prominent GFP-specific RNA of sense or antisense polarity, indicating that the RNA species which induced silencing was present only in low concentration or did not hybridize due to formation of an intramolecular double strand. In view of its high activity, it is possible that this agent is responsible for the systemic spread of silencing in plants and it might represent the aberrant RNA, a previously postulated inducer of silencing.

Animals↗
PubMed2002

Caloric restriction and lifespan: a role for protein turnover?

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.

Aging↗
PubMed2002

Death by necrosis. Uncontrollable catastrophe, or is there order behind the chaos?

Cells suffer necrotic death when exposed to extreme environmental conditions, adverse and excessive stimuli, or when deleterious mutations are encoded in their genetic material. Unlike apoptosis, which involves a highly regulated and elaborate network of biochemical events and cascades, necrosis has been considered generally to be a chaotic decadence process that effects the inexorable demise of cells otherwise not destined to die. This grim prospect is now slowly being overturned, mostly by exciting new findings in two simple model organisms, Caenorhabditis elegans and Drosophila melanogaster. Despite the wide spectrum of necrosis-initiating conditions, evidence is accumulating that execution of necrotic or neurodegenerative cell death may be carried out by a finite common set of mechanisms.

Animals↗
PubMedDate not supplied

Imaging of Caenorhabditis elegans neurons by second-harmonic generation and two-photon excitation fluorescence.

Second-harmonic generation (SHG) and two-photon excitation fluorescence (TPEF) are relatively new and promising tools for the detailed imaging of biological samples and processes at the microscopic level. By exploiting these nonlinear phenomena phototoxicity and photobleaching effects on the specimens are reduced dramatically. The main target of this work was the development of a compact inexpensive and reliable experimental apparatus for nonlinear microscopy measurements. Femtosecond laser pulses were utilized for excitation. We achieved high-resolution imaging and mapping of Caenorhabditis elegans (C. elegans) neurons and muscular structures of the pharynx, at the microscopic level by performing SHG and TPEF measurements. By detecting nonlinear phenomena such as SHG and TPEF it is feasible to extract valuable information concerning the structure and the function of nematode neurons.

Animals↗
PubMedDate not supplied

First identification of a phosphorylcholine-substituted protein from Caenorhabditis elegans: isolation and characterization of the aspartyl protease ASP-6.

Caenorhabditis elegans is a widely accepted model system for parasitic nematodes, drug screening and developmental studies. Similar to parasitic worms, C. elegans expresses glycosphingolipids and glycoproteins carrying, in part, phosphorylcholine (PCho) substitutions, which might play important roles in nematode development, fertility and, at least in the case of parasites, survival within the host. With the exception of a major secretory/excretory product from Acanthocheilonema viteae (ES-62), no protein carrying this epitope has been studied in detail yet. Here we report on the identification, characterization and localization of the aspartyl protease ASP-6 of C. elegans, which is excreted by the nematode in a PCho-substituted form. Within the worm, most prominent expression of the protein is observed in the intestine, while muscle and epithelial cells express asp-6 to a lesser extent. In animals harboring an ASP-6::GFP fusion protein, diffuse fluorescence throughout the body cavity of adult worms indicates that the chimeric protein is secreted.

Amino Acid Sequence↗