Zhang S et al. (2020) Front Endocrinol (Lausanne) "Caenorhabditis elegans as a Useful Model for Studying Aging Mutations."

Zhang S, Li Z, Zhou T, Wang G, Li F

[Front Endocrinol (Lausanne), 2020]

The <i>Caenorhabditis elegans</i> genome possesses homologs of about two-thirds of all human disease genes. Based on its physiological aging characteristics and superiority, the use of <i>C. elegans</i> as a model system for studies on aging, age-related diseases, mechanisms of longevity, and drug screening has been widely acknowledged in recent decades. Lifespan increasing mutations in <i>C. elegans</i> were found to delay aging by impinging several signaling pathways and related epigenetic modifications, including the insulin/IGF-1 signaling (IIS), AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR) pathways. Interestingly, dietary restriction (DR) has been shown to increase the lifespan of numerous metazoans and protect them from multiple age-related pathologies. However, the underlying molecular mechanisms are unclear. In recent decades, <i>C. elegans</i> has been used as a unique model system for high-throughput drug screening. Here, we review <i>C. elegans</i> mutants exhibiting increased in lifespan and age-dependent changes under DR, as well as the utility of <i>C. elegans</i> for drug screening. Thus, we provide evidence for the use of this model organism in research on the prevention of aging.

Meng L et al. (2013) J Genet Genomics "Roles of microRNAs in the Caenorhabditis elegans nervous system."

Chen L, Li Z, Wu ZX, Meng L, Shan G

[J Genet Genomics, 2013]

The first microRNA was discovered in Caenorhabditis elegans in 1993, and since then, thousands of microRNAs have been identified from almost all eukaryotic organisms examined. MicroRNAs function in many biological events such as cell fate determination, metabolism, apoptosis, and carcinogenesis. So far, more than 250 microRNAs have been identified in C. elegans; however, functions for most of these microRNAs are still unknown. A small number of C. elegans microRNAs are associated with known physiological roles such as developmental timing, cell differentiation, stress response, and longevity. In this review, we summarize known roles of microRNAs in neuronal differentiation and function of C. elegans, and discuss interesting perspectives for future studies.

Wu Y et al. (2023) Int J Mol Sci "Towards Understanding Neurodegenerative Diseases: Insights from Caenorhabditis elegans."

Yu X, Wu Y, Zhang M, Li Z, Chen Y

[Int J Mol Sci, 2023]

The elevated occurrence of debilitating neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD) and Machado-Joseph disease (MJD), demands urgent disease-modifying therapeutics. Owing to the evolutionarily conserved molecular signalling pathways with mammalian species and facile genetic manipulation, the nematode <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) emerges as a powerful and manipulative model system for mechanistic insights into neurodegenerative diseases. Herein, we review several representative <i>C. elegans</i> models established for five common neurodegenerative diseases, which closely simulate disease phenotypes specifically in the gain-of-function aspect. We exemplify applications of high-throughput genetic and drug screenings to illustrate the potential of <i>C. elegans</i> to probe novel therapeutic targets. This review highlights the utility of <i>C. elegans</i> as a comprehensive and versatile platform for the dissection of neurodegenerative diseases at the molecular level.

Lecroisey C et al. (2007) J Muscle Res Cell Motil "The C. elegans dense body: anchoring and signaling structure of the muscle."

Gieseler K, Lecroisey C, Segalat L

[J Muscle Res Cell Motil, 2007]

During evolution, both the architecture and the cellular physiology of muscles have been remarkably maintained. Striated muscles of invertebrates, although less complex, strongly resemble vertebrate skeletal muscles. In particular, the basic contractile unit called the sarcomere is almost identical between vertebrates and invertebrates. In vertebrate muscles, sarcomeric actin filaments are anchored to attachment points called Z-disks, which are linked to the extra-cellular matrix (ECM) by a muscle specific focal adhesion site called the costamere. In this review, we focus on the dense body of the animal model Caenorhabditis elegans. The C. elegans dense body is a structure that performs two in one roles at the same time, that of the Z-disk and of the costamere. The dense body is anchored in the muscle membrane and provides rigidity to the muscle by mechanically linking actin filaments to the ECM. In the last few years, it has become increasingly evident that, in addition to its structural role, the dense body also performs a signaling function in muscle cells. In this paper, we review recent advances in the understanding of the C. elegans dense body composition and function.

Qadota H et al. (2010) J Biomed Biotechnol "Molecular structure of sarcomere-to-membrane attachment at M-Lines in C. elegans muscle."

Qadota H, Benian GM

[J Biomed Biotechnol, 2010]

C. elegans is an excellent model for studying nonmuscle cell focal adhesions and the analogous muscle cell attachment structures. In the major striated muscle of this nematode, all of the M-lines and the Z-disk analogs (dense bodies) are attached to the muscle cell membrane and underlying extracellular matrix. Accumulating at these sites are many proteins associated with integrin. We have found that nematode M-lines contain a set of protein complexes that link integrin-associated proteins to myosin thick filaments. We have also obtained evidence for intriguing additional functions for these muscle cell attachment proteins.

Ziegler C (1994) Comp Biochem Physiol A Physiol "Titin-related proteins in invertebrate muscles."

Ziegler C

[Comp Biochem Physiol A Physiol, 1994]

The localization of filaments connecting the Z-line and the A-band in insect flight muscles and the identification of very large proteins as their components is reviewed. The characterization of twitchin in the obliquely striated muscles of Caenorhabditis elegans is reported and the deductions made from its amino acid sequence are considered. The characterization of mini-titins in obliquely striated molluscan muscles is compared. The identification of projectin in the muscles of Drosophila melanogaster by anti-twitchin-antibodies, its sequence analysis and the characterization of mini-titins in arthropod and mollusc fast-striated muscles are summarized. The possible biological functions of the different proteins in various invertebrate muscles are discussed.

Bullard B et al. (2002) J Muscle Res Cell Motil "Varieties of elastic protein in invertebrate muscles."

Leonard K, Linke WA, Bullard B

[J Muscle Res Cell Motil, 2002]

Elastic proteins in the muscles of a nematode (Caenorhabditis elegans), three insects (Drosophila melanogaster, Anopheles gambiae, Bombyx mori) and a crustacean (Procambus clarkii) were compared. The sequences of thick filament proteins, twitchin in the worm and projectin in the insects, have repeating modules with fibronectin-like (Fn) and immunoglobulin-like (Ig) domains conserved between species. Projectin has additional tandem Igs and an elastic PEVK domain near the N-terminus. All the species have a second elastic protein we have called SLS protein after the Drosophila gene, sallimus. SLS protein is in the I-band. The N-terminal region has the sequence of kettin which is a spliced product of the gene composed of Ig-linker modules binding to actin. Downstream of kettin, SLS protein has two PEVK domains, unique sequence, tandem Igs, and Fn domains at the end. PEVK domains have repeating sequences: some are long and highly conserved and would have varying elasticity appropriate to different muscles. Insect indirect flight muscle (IFM) has short I-bands and electron micrographs of Lethocerus IFM show fine filaments branching from the end of thick filaments to join thin filaments before they enter the Z-disc. Projectin and kettin are in this region and the contribution of these to the high passive stiffness of Drosophila IFM myofibrils was measured from the force response to length oscillations. Kettin is attached both to actin near the Z-disc and to the end of thick filaments, and extraction of actin or digestion of kettin leads to rapid decrease in stiffness; residual tension is attributable to projectin. The wormlike chain model for polymer elasticity fitted the force-extension curve of IFM myofibrils and the number of predicted Igs in the chain is consistent with the tandem Igs in Drosophila SLS protein. We conclude that passive tension is due to kettin and projectin, either separate or

Lucchesi JC (2018) J Genet "Transcriptional modulation of entire chromosomes: dosage compensation."

Lucchesi JC

[J Genet, 2018]

Dosage compensation is a regulatory system designed to equalize the transcription output of the genes of the sex chromosomes that are present in different doses in the sexes (X or Z chromosome, depending on the animal species involved). Different mechanisms of dosage compensation have evolved in different animal groups. In Drosophila males, a complex (male-specific lethal) associates with the X chromosome and enhances the activity of most X-linked genes by increasing the rate of RNAPII elongation. In Caenorhabditis, a complex (dosage compensation complex) that contains a number of proteins involved in condensing chromosomes decreases the level of transcription of both X chromosomes in the XX hermaphrodite. In mammals, dosage compensation is achieved by the inactivation, early during development, of most X-linked genes on one of the two X chromosomes in females. The mechanism involves the synthesis of an RNA (Tsix) that protects one of the two Xs from inactivation, and of another RNA (Xist) that coats the other X chromosome and recruits histone and DNA modifying enzymes. This review will focus on the current progress in understanding the dosage compensation mechanisms in the three taxa where it has been best studied at the molecular level: flies, round worms and mammals.

Serio TR et al. (2001) Adv Protein Chem "[PSI+], SUP35, and chaperones."

Serio TR, Lindquist SL

[Adv Protein Chem, 2001]

Biochemical characterization of the yeast prions has revealed many similarities with the mammalian amyloidogenic proteins. The ease of generating in vivo mutations in yeast and the developing in vitro models for [PSI+] and [URE3] circumvent many of the difficulties of studying the proteins linked to the mammalian amyloidoses. Future work especially aimed at understanding the molecular role of chaperone proteins in regulating conversion as well as the early steps in de novo formation of the prion state in yeast will likely provide invaluable lessons that may be more broadly applicable to related processes in higher eukaryotes. It is important to remember, however, that there are clear distinctions between disease states associated with amyloidogenesis and the epigenetic modulation of protein function by self-perpetuating conformational conversions. Amyloid formation is detrimental to mammals and is likely selected against, providing a possible explanation for the late onset of these disorders (Lansbury, 1999). In contrast, the known yeast prions are compatible with normal growth and, if beneficial to the organism, may be subject to evolutionary pressures that ultimately maximize transmission. In the prion proteins examined to date, distinct domains are responsible for normal function and for the conformational switches producing a prion conversion of that function. Recent work has demonstrated that the prion domains are both modular and transferable to other proteins on which they can confer a heritable epigenetic alteration of function (Edskes et al., 1999; Li and Lindquist, 2000; Patino et al., 1996; Santoso et al., 2000; Sondheimer and Lindquist, 2000). That is, prion domains need not coevolve with particular functional domains but might be moved from one protein to another during evolution. Such processes may be widely used in biology. Mechanistic studies of [PSI+] and [URE3] replication are sure to lay a foundation of knowledge for understanding a host of nonconventional genetic elements that currently remain elusive.

Lytton J (2007) Biochem J "Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport."

Lytton J

[Biochem J, 2007]

Mammalian Na+/Ca2+ exchangers are members of three branches of a much larger family of transport proteins [the CaCA (Ca2+/cation antiporter) superfamily] whose main role is to provide control of Ca2+ flux across the plasma membranes or intracellular compartments. Since cytosolic levels of Ca2+ are much lower than those found extracellularly or in sequestered stores, the major function of Na+/Ca2+ exchangers is to extrude Ca2+ from the cytoplasm. The exchangers are, however, fully reversible and thus, under special conditions of subcellular localization and compartmentalized ion gradients, Na+/Ca2+ exchangers may allow Ca2+ entry and may play more specialized roles in Ca2+ movement between compartments. The NCX (Na+/Ca2+ exchanger) [SLC (solute carrier) 8] branch of Na+/Ca2+ exchangers comprises three members: NCX1 has been most extensively studied, and is broadly expressed with particular abundance in heart, brain and kidney, NCX2 is expressed in brain, and NCX3 is expressed in brain and skeletal muscle. The NCX proteins subserve a variety of roles, depending upon the site of expression. These include cardiac excitation-contraction coupling, neuronal signalling and Ca2+ reabsorption in the kidney. The NCKX (Na2+/Ca2+-K+ exchanger) (SLC24) branch of Na+/Ca2+ exchangers transport K+ and Ca2+ in exchange for Na+, and comprises five members: NCKX1 is expressed in retinal rod photoreceptors, NCKX2 is expressed in cone photoreceptors and in neurons throughout the brain, NCKX3 and NCKX4 are abundant in brain, but have a broader tissue distribution, and NCKX5 is expressed in skin, retinal epithelium and brain. The NCKX proteins probably play a particularly prominent role in regulating Ca2+ flux in environments which experience wide and frequent fluctuations in Na+ concentration. Until recently, the range of functions that NCKX proteins play was generally underappreciated. This situation is now changing rapidly as evidence emerges for roles including photoreceptor adaptation, synaptic plasticity and skin pigmentation. The CCX (Ca2+/cation exchanger) branch has only one mammalian member, NCKX6 or NCLX (Na+/Ca2+-Li+ exchanger), whose physiological function remains unclear, despite a broad pattern of expression.