Aging and Neurodegeneration: New Approaches to Neurodegeneration and Aging

Abstract Model organisms like C. elegans and Drosophila are powerful systems to help dissect molecular genetic aspects of complex biological processes. Here we will present a number of biological questions and approaches that have been used to study questions of neural integrity and healthful aging using these systems.

Download Full-text

The near demise and subsequent revival of classical genetics for investigating Caenorhabditis elegans embryogenesis: RNAi meets next-generation DNA sequencing

Molecular Biology of the Cell ◽

10.1091/mbc.e11-03-0185 ◽

2011 ◽

Vol 22 (19) ◽

pp. 3556-3558 ◽

Cited By ~ 3

Author(s):

Bruce Bowerman

Keyword(s):

Caenorhabditis Elegans ◽

Dna Sequencing ◽

Reverse Genetics ◽

Molecular Genetic ◽

Biological Processes ◽

Next Generation ◽

Next Generation Dna Sequencing ◽

C Elegans ◽

Sequencing Technologies ◽

Classical Genetics

Molecular genetic investigation of the early Caenorhabditis elegans embryo has contributed substantially to the discovery and general understanding of the genes, pathways, and mechanisms that regulate and execute developmental and cell biological processes. Initially, worm geneticists relied exclusively on a classical genetics approach, isolating mutants with interesting phenotypes after mutagenesis and then determining the identity of the affected genes. Subsequently, the discovery of RNA interference (RNAi) led to a much greater reliance on a reverse genetics approach: reducing the function of known genes with RNAi and then observing the phenotypic consequences. Now the advent of next-generation DNA sequencing technologies and the ensuing ease and affordability of whole-genome sequencing are reviving the use of classical genetics to investigate early C. elegans embryogenesis.

Download Full-text

Apoptosis and development

Essays in Biochemistry ◽

10.1042/bse0390011 ◽

2003 ◽

Vol 39 ◽

pp. 11-24 ◽

Cited By ~ 6

Author(s):

Justin V McCarthy

Keyword(s):

Drosophila Melanogaster ◽

Mammalian Cells ◽

Cell Number ◽

Model Organisms ◽

Biological Processes ◽

Nematode Caenorhabditis Elegans ◽

Apoptotic Pathway ◽

Genetic Pathways ◽

Evolutionarily Conserved ◽

Multicellular Organisms

Apoptosis is an evolutionarily conserved process used by multicellular organisms to developmentally regulate cell number or to eliminate cells that are potentially detrimental to the organism. The large diversity of regulators of apoptosis in mammalian cells and their numerous interactions complicate the analysis of their individual functions, particularly in development. The remarkable conservation of apoptotic mechanisms across species has allowed the genetic pathways of apoptosis determined in lower species, such as the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster, to act as models for understanding the biology of apoptosis in mammalian cells. Though many components of the apoptotic pathway are conserved between species, the use of additional model organisms has revealed several important differences and supports the use of model organisms in deciphering complex biological processes such as apoptosis.

Download Full-text

The glycomes of Caenorhabditis elegans and other model organisms

Biochemical Society Symposium ◽

10.1042/bss0690117 ◽

2002 ◽

Vol 69 ◽

pp. 117-134 ◽

Cited By ~ 47

Author(s):

Stuart M. Haslam ◽

David Gems ◽

Howard R. Morris ◽

Anne Dell

Keyword(s):

Caenorhabditis Elegans ◽

Current Knowledge ◽

Structural Data ◽

Model Organisms ◽

Entire Genome ◽

C Elegans ◽

The Face ◽

Area Of Concern ◽

Nematode Worm

There is no doubt that the immense amount of information that is being generated by the initial sequencing and secondary interrogation of various genomes will change the face of glycobiological research. However, a major area of concern is that detailed structural knowledge of the ultimate products of genes that are identified as being involved in glycoconjugate biosynthesis is still limited. This is illustrated clearly by the nematode worm Caenorhabditis elegans, which was the first multicellular organism to have its entire genome sequenced. To date, only limited structural data on the glycosylated molecules of this organism have been reported. Our laboratory is addressing this problem by performing detailed MS structural characterization of the N-linked glycans of C. elegans; high-mannose structures dominate, with only minor amounts of complex-type structures. Novel, highly fucosylated truncated structures are also present which are difucosylated on the proximal N-acetylglucosamine of the chitobiose core as well as containing unusual Fucα1–2Gal1–2Man as peripheral structures. The implications of these results in terms of the identification of ligands for genomically predicted lectins and potential glycosyltransferases are discussed in this chapter. Current knowledge on the glycomes of other model organisms such as Dictyostelium discoideum, Saccharomyces cerevisiae and Drosophila melanogaster is also discussed briefly.

Download Full-text

Myosinome: A Database of Myosins from Select Eukaryotic Genomes to Facilitate Analysis of Sequence-Structure-Function Relationships

Bioinformatics and Biology Insights ◽

10.4137/bbi.s9902 ◽

2012 ◽

Vol 6 ◽

pp. BBI.S9902 ◽

Cited By ~ 3

Author(s):

Divya P. Syamaladevi ◽

Margaret S Sunitha ◽

S. Kalaimathy ◽

Chandrashekar C. Reddy ◽

Mohammed Iftekhar ◽

...

Keyword(s):

Conformational Changes ◽

Atp Hydrolysis ◽

Homo Sapiens ◽

Relevant Literature ◽

Myosin Ii ◽

Coiled Coil ◽

Structural Features ◽

Model Organisms ◽

Congenital Diseases ◽

C Elegans

Myosins are one of the largest protein superfamilies with 24 classes. They have conserved structural features and catalytic domains yet show huge variation at different domains resulting in a variety of functions. Myosins are molecules driving various kinds of cellular processes and motility until the level of organisms. These are ATPases that utilize the chemical energy released by ATP hydrolysis to bring about conformational changes leading to a motor function. Myosins are important as they are involved in almost all cellular activities ranging from cell division to transcriptional regulation. They are crucial due to their involvement in many congenital diseases symptomatized by muscular malfunctions, cardiac diseases, deafness, neural and immunological dysfunction, and so on, many of which lead to death at an early age. We present Myosinome, a database of selected myosin classes (myosin II, V, and VI) from five model organisms. This knowledge base provides the sequences, phylogenetic clustering, domain architectures of myosins and molecular models, structural analyses, and relevant literature of their coiled-coil domains. In the current version of Myosinome, information about 71 myosin sequences belonging to three myosin classes (myosin II, V, and VI) in five model organisms ( Homo Sapiens, Mus musculus, D. melanogaster, C. elegans and S. cereviseae) identified using bioinformatics surveys are presented, and several of them are yet to be functionally characterized. As these proteins are involved in congenital diseases, such a database would be useful in short-listing candidates for gene therapy and drug development. The database can be accessed from http://caps.ncbs.res.in/myosinome .

Download Full-text

Educational Attainment and Personality Are Genetically Intertwined

Psychological Science ◽

10.1177/0956797617719083 ◽

2017 ◽

Vol 28 (11) ◽

pp. 1631-1639 ◽

Cited By ~ 21

Author(s):

René Mõttus ◽

Anu Realo ◽

Uku Vainik ◽

Jüri Allik ◽

Tõnu Esko

Keyword(s):

Educational Attainment ◽

Personality Traits ◽

Personality Trait ◽

Factor Model ◽

Five Factor Model ◽

Molecular Genetic ◽

Maximum Amount ◽

Biological Processes ◽

Psychological Traits ◽

Polygenic Scores

Heritable variance in psychological traits may reflect genetic and biological processes that are not necessarily specific to these particular traits but pertain to a broader range of phenotypes. We tested the possibility that the personality domains of the five-factor model and their 30 facets, as rated by people themselves and their knowledgeable informants, reflect polygenic influences that have been previously associated with educational attainment. In a sample of more than 3,000 adult Estonians, education polygenic scores (EPSs), which are interpretable as estimates of molecular-genetic propensity for education, were correlated with various personality traits, particularly from the neuroticism and openness domains. The correlations of personality traits with phenotypic educational attainment closely mirrored their correlations with EPS. Moreover, EPS predicted an aggregate personality trait tailored to capture the maximum amount of variance in educational attainment almost as strongly as it predicted the attainment itself. We discuss possible interpretations and implications of these findings.

Download Full-text

Deficiency of innate immunity against P. aeruginosa enhances behavioral avoidance via the HECW-1/NPR-1 module in C. elegans

Infection and Immunity ◽

10.1128/iai.00067-21 ◽

2021 ◽

Author(s):

Hua Bai ◽

Wei Zou ◽

Wenhui Zhou ◽

Keqin Zhang ◽

Xiaowei Huang

Keyword(s):

Innate Immunity ◽

Pathogenic Bacteria ◽

Immune Gene ◽

Biological Processes ◽

Defensive Strategy ◽

C Elegans ◽

Defensive Strategies ◽

Behavioral Avoidance ◽

Neuropeptide Y Receptor ◽

G Protein Coupled

To antagonize infection of pathogenic bacteria in soil and confer increased survival, Caenorhabditis elegans employs innate immunity and behavioral avoidance synchronously as the two main defensive strategies. Although both biological processes and their individual signaling pathways have been partially elucidated, knowledge of their interrelationship remains limited. The current study reveals that deficiency of innate immunity triggered by mutation of the classic immune gene pmk-1 promotes avoidance behavior in C. elegans ; and vice versa. Restoration of pmk-1 expression using the tissue-specific promoters suggested that the functional loss of both intestinal and neuronal pmk-1 is necessary for the enhanced avoidance. Additionally, PMK-1 co-localized with the E3 ubiquitin ligase HECW-1 in OLL neurons and regulated the expressional level of the latter, which consequently affected the production of NPR-1, a G-protein-coupled receptor homologous to the mammalian neuropeptide Y receptor, in RMG neurons in a non-cell-autonomous manner. Collectively, our study illustrates, once the innate immunity is impaired when C. elegans antagonizes bacterial infection, the other defensive strategy of behavioral avoidance can be enhanced accordingly via the HECW-1/NPR-1 module, suggesting that GPCRs in neural circuits may receive the inputs from immune system and integrate those two systems for better adapting to the real-time status.

Download Full-text

Hidden in plain sight: What remains to be discovered in the eukaryotic proteome?

10.1101/469569 ◽

2018 ◽

Author(s):

Valerie Wood ◽

Antonia Lock ◽

Midori A. Harris ◽

Kim Rutherford ◽

Jürg Bähler ◽

...

Keyword(s):

Gene Ontology ◽

Fission Yeast ◽

Genome Sequencing ◽

Large Scale ◽

Biological Process ◽

Blind Spot ◽

Model Organisms ◽

Biological Processes ◽

Health And Disease

AbstractThe first decade of genome sequencing stimulated an explosion in the characterization of unknown proteins. More recently, the pace of functional discovery has slowed, leaving around 20% of the proteins even in well-studied model organisms without informative descriptions of their biological roles. Remarkably, many uncharacterized proteins are conserved from yeasts to human, suggesting that they contribute to fundamental biological processes. To fully understand biological systems in health and disease, we need to account for every part of the system. Unstudied proteins thus represent a collective blind spot that limits the progress of both basic and applied biosciences.We use a simple yet powerful metric based on Gene Ontology (GO) biological process terms to define characterized and uncharacterized proteins for human, budding yeast, and fission yeast. We then identify a set of conserved but unstudied proteins in S. pombe, and classify them based on a combination of orthogonal attributes determined by large-scale experimental and comparative methods. Finally, we explore possible reasons why these proteins remain neglected, and propose courses of action to raise their profile and thereby reap the benefits of completing the catalog of proteins’ biological roles.

Download Full-text

Multi-environment phenotyping of C. elegans for robust evaluation of physical performance

10.1101/2020.08.17.253583 ◽

2020 ◽

Author(s):

Jennifer E. Hewitt ◽

Ricardo Laranjeiro ◽

Masoud Norouzi ◽

Rebecca Ellwood ◽

Adam Antebi ◽

...

Keyword(s):

Muscular Dystrophy ◽

Physical Performance ◽

Current Treatment ◽

Therapeutic Interventions ◽

Model Organisms ◽

C Elegans ◽

Drug Candidates ◽

Treatment Standard ◽

Drug Interventions

ABSTRACTDetermining the physical performance of humans using several measures is essential to evaluating the severity of diseases, understanding the role of environmental factors, and developing therapeutic interventions. Development of analogous measures of physical performance in model organisms can help in identifying conserved signaling pathways and prioritizing drug candidates. In this study, we propose a multi-environment phenotyping (MEP) approach that generates a comprehensive set of measures indicative of physical performance in C. elegans. We challenge C. elegans in different mechanical environments of burrowing, swimming, and crawling, each of which places different physiological demands on the animals to generate locomotory forces. Implementation of the MEP approach is done using three established assays corresponding to each environment–a hydrogel-based burrowing assay, the CeleST swim assay, and the NemaFlex crawling strength assay. Using this approach, we study individuals and show that these three assays report on unique aspects of nematode physiology, as phenotypic measures obtained from different environments do not correlate with one another. Analysis of a subset of genes representative of oxidative stress, glucose metabolism, and fat metabolism show differential expression depending on the animal’s environment, suggesting that each environment evokes a response with distinct genetic requirements. To demonstrate the utility of the MEP platform, we evaluate the response of a muscular dystrophy model of C. elegans dys-1 to drug interventions of prednisone, melatonin and serotonin. We find that prednisone, which is the current treatment standard for human Duchenne muscular dystrophy, confers benefits in all three assays. Furthermore, while the tested compounds improve the physical performance of dys-1, these compounds are not able to fully restore the measures to wild-type levels, suggesting the need for discovery efforts to identify more efficacious compounds that could be aided using the MEP platform. In summary, the MEP platform’s ability to robustly define C. elegans locomotory phenotypes demonstrates the utility of the MEP approach toward identification of candidates for therapeutic intervention, especially in disease models in which the neuromuscular performance is impaired.

Download Full-text

Identification of high-efficiency 3′GG gRNA motifs in indexed FASTA files with ngg2

PeerJ Computer Science ◽

10.7717/peerj-cs.33 ◽

2015 ◽

Vol 1 ◽

pp. e33 ◽

Cited By ~ 2

Author(s):

Elisha D. Roberson

Keyword(s):

High Efficiency ◽

Homo Sapiens ◽

Model Organisms ◽

Proof Of Concept ◽

Protein Coding ◽

C Elegans ◽

Protein Coding Genes ◽

Starting Point ◽

Command Line Tool ◽

Reference Genomes

CRISPR/Cas9 is emerging as one of the most-used methods of genome modification in organisms ranging from bacteria to human cells. However, the efficiency of editing varies tremendously site-to-site. A recent report identified a novel motif, called the 3′GG motif, which substantially increases the efficiency of editing at all sites tested inC. elegans. Furthermore, they highlighted that previously published gRNAs with high editing efficiency also had this motif. I designed a Python command-line tool, ngg2, to identify 3′GG gRNA sites from indexed FASTA files. As a proof-of-concept, I screened for these motifs in six model genomes:Saccharomyces cerevisiae,Caenorhabditis elegans,Drosophila melanogaster,Danio rerio,Mus musculus, andHomo sapiens. I also scanned the genomes of pig (Sus scrofa) and African elephant (Loxodonta africana) to demonstrate the utility in non-model organisms. I identified more than 60 million single match 3′GG motifs in these genomes. Greater than 61% of all protein coding genes in the reference genomes had at least one unique 3′GG gRNA site overlapping an exon. In particular, more than 96% of mouse and 93% of human protein coding genes have at least one unique, overlapping 3′GG gRNA. These identified sites can be used as a starting point in gRNA selection, and the ngg2 tool provides an important ability to identify 3′GG editing sites in any species with an available genome sequence.

Download Full-text

C. elegans neurons have functional dendritic spines

eLife ◽

10.7554/elife.47918 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 4

Author(s):

Andrea Cuentas-Condori ◽

Ben Mulcahy ◽

Siwei He ◽

Sierra Palumbos ◽

Mei Zhen ◽

...

Keyword(s):

Motor Neurons ◽

Dendritic Spines ◽

Live Cell Imaging ◽

Cell Imaging ◽

Super Resolution ◽

Live Cell ◽

Model Organisms ◽

Spine Density ◽

C Elegans ◽

Spine Function

Dendritic spines are specialized postsynaptic structures that transduce presynaptic signals, are regulated by neural activity and correlated with learning and memory. Most studies of spine function have focused on the mammalian nervous system. However, spine-like protrusions have been reported in C. elegans (Philbrook et al., 2018), suggesting that the experimental advantages of smaller model organisms could be exploited to study the biology of dendritic spines. Here, we used super-resolution microscopy, electron microscopy, live-cell imaging and genetics to show that C. elegans motor neurons have functional dendritic spines that: (1) are structurally defined by a dynamic actin cytoskeleton; (2) appose presynaptic dense projections; (3) localize ER and ribosomes; (4) display calcium transients triggered by presynaptic activity and propagated by internal Ca++ stores; (5) respond to activity-dependent signals that regulate spine density. These studies provide a solid foundation for a new experimental paradigm that exploits the power of C. elegans genetics and live-cell imaging for fundamental studies of dendritic spine morphogenesis and function.

Download Full-text