Exploring the conservation of Alzheimer-related pathways between H. sapiens and C. elegans: a network alignment approach

AbstractAlzheimer disease (AD) is a neurodegenerative disorder with an –as of yet– unclear etiology and pathogenesis. Research to unveil disease processes underlying AD often relies on the use of neurodegenerative disease model organisms, such as Caenorhabditis elegans. This study sought to identify biological pathways implicated in AD that are conserved in Homo sapiens and C. elegans. Protein–protein interaction networks were assembled for amyloid precursor protein (APP) and Tau in H. sapiens—two proteins whose aggregation is a hallmark in AD—and their orthologs APL-1 and PTL-1 for C. elegans. Global network alignment was used to compare these networks and determine similar, likely conserved, network regions. This comparison revealed that two prominent pathways, the APP-processing and the Tau-phosphorylation pathways, are highly conserved in both organisms. While the majority of interactions between proteins in those pathways are known to be associated with AD in human, they remain unexamined in C. elegans, signifying the need for their further investigation. In this work, we have highlighted conserved interactions related to AD in humans and have identified specific proteins that can act as targets for experimental studies in C. elegans, aiming to uncover the underlying mechanisms of AD.

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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 .

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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.

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

10.7287/peerj.preprints.969v2 ◽

2015 ◽

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 in C. 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, and Homo 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.

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

10.7287/peerj.preprints.969 ◽

2015 ◽

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 in C. 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, and Homo 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.

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Sulfurous Gases As Biological Messengers and Toxins: Comparative Genetics of Their Metabolism in Model Organisms

Journal of Toxicology ◽

10.1155/2011/394970 ◽

2011 ◽

Vol 2011 ◽

pp. 1-14 ◽

Cited By ~ 26

Author(s):

Neal D. Mathew ◽

David I. Schlipalius ◽

Paul R. Ebert

Keyword(s):

Homo Sapiens ◽

Biological Activities ◽

Model Organisms ◽

Homologous Proteins ◽

C Elegans ◽

Signalling Molecules ◽

Reducing Conditions ◽

Mercaptopyruvate Sulfurtransferase ◽

Sulfurous Compounds ◽

Sulfur Containing

Gasotransmitters are biologically produced gaseous signalling molecules. As gases with potent biological activities, they are toxic as air pollutants, and the sulfurous compounds are used as fumigants. Most investigations focus on medical aspects of gasotransmitter biology rather than toxicity toward invertebrate pests of agriculture. In fact, the pathways for the metabolism of sulfur containing gases in lower organisms have not yet been described. To address this deficit, we use protein sequences fromHomo sapiensto query Genbank for homologous proteins inCaenorhabditis elegans,Drosophila melanogaster, andSaccharomyces cerevisiae. InC. elegans, we find genes for all mammalian pathways for synthesis and catabolism of the three sulfur containing gasotransmitters, H2S, SO2and COS. The genes for H2S synthesis have actually increased in number inC. elegans. Interestingly,D. melanogasterand Arthropoda in general, lack a gene for 3-mercaptopyruvate sulfurtransferase, an enzym for H2S synthesis under reducing conditions.

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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.

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Mechanisms underlying heart failure in type 2 diabetes mellitus

Heart and Metabolism - Heart Failure in patients with Diabetes ◽

10.31887/hm.2019.80/hbugger ◽

2019 ◽

pp. 37-39

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Experimental Studies ◽

Vascular Complications ◽

Molecular Alterations ◽

Increased Risk ◽

Cardioprotective Effects ◽

Underlying Mechanisms ◽

Cardio Vascular

The prevalence of heart failure is markedly increased in individuals with diabetes mellitus. Numerous observational studies suggest that this increased risk for heart failure can be attributed to exacerbated vascular complications and the presence of increased risk factors in diabetic subjects. In addition, experimental studies revealed the presence of a number of distinct molecular alterations in the myocardium that occur independently of vascular disease and hypertension. Many of these molecular alterations are similarly observed in failing hearts of nondiabetic patients and have thus been proposed to contribute to the increased risk for heart failure in diabetes. The interest in understanding the underlying mechanisms of impaired cardio- vascular outcomes in diabetic individuals has much increased since the demonstration of cardioprotective effects of SGLT-2 inhibitors and GLP-1 receptor agonists in recent clinical trials. The current review therefore summarizes the distinct mechanisms that have been proposed to increase the risk for heart failure in diabetes mellitus.

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In silico and In vivo Evaluation of Oxidative Stress Inhibitors Against Parkinson`s Disease using the C. elegans Model

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666200514074128 ◽

2020 ◽

Vol 23 (8) ◽

pp. 814-826

Author(s):

Pradeep Hanumanthappa ◽

Arpitha Ashok ◽

Inderjit Prakash ◽

Carmel I. Priya ◽

Julie Zinzala ◽

...

Keyword(s):

Neuronal Death ◽

Neurodegenerative Disorder ◽

In Vivo Evaluation ◽

Neuroprotective Effects ◽

Ample Evidence ◽

C Elegans ◽

Rational Drug ◽

Cullin 3 ◽

Anti Oxidant

Background: Parkinson’s disease ranks second, after Alzheimer’s as the major neurodegenerative disorder, for which no cure or disease-modifying therapies exist. Ample evidence indicate that PD manifests as a result of impaired anti-oxidative machinery leading to neuronal death wherein Cullin-3 has ascended as a potential therapeutic target for diseases involving damaged anti-oxidative machinery. Objective: The design of target specific inhibitors for the Cullin-3 protein might be a promising strategy to increase the Nrf2 levels and to decrease the possibility of “off-target” toxic properties. Methods: In the present study, an integrated computational and wet lab approach was adopted to identify small molecule inhibitors for Cullin-3. The rational drug designing process comprised homology modeling and derivation of the pharmacophore for Cullin-3, virtual screening of Zinc natural compound database, molecular docking and Molecular dynamics based screening of ligand molecules. In vivo validations of an identified lead compound were conducted in the PD model of C. elegans. Results and Discussion: Our strategy yielded a potential inhibitor; (Glide score = -12.31), which was evaluated for its neuroprotective efficacy in the PD model of C. elegans. The inhibitor was able to efficiently defend against neuronal death in PD model of C. elegans and the neuroprotective effects were attributed to its anti-oxidant activities, supported by the increase in superoxide dismutase, catalase and the diminution of acetylcholinesterase and reactive oxygen species levels. In addition, the Cullin-3 inhibitor significantly restored the behavioral deficits in the transgenic C. elegans. Conclusion: Taken together, these findings highlight the potential utility of Cullin-3 inhibition to block the persistent neuronal death in PD. Further studies focusing on Cullin-3 and its mechanism of action would be interesting.

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Cross-Predicting Essential Genes between Two Model Eukaryotic Species Using Machine Learning

International Journal of Molecular Sciences ◽

10.3390/ijms22105056 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5056

Author(s):

Tulio L. Campos ◽

Pasi K. Korhonen ◽

Neil D. Young

Keyword(s):

Machine Learning ◽

Experimental Studies ◽

Essential Genes ◽

Subcellular Localisation ◽

Cross Prediction ◽

Gene Essentiality ◽

C Elegans ◽

Cellular Processes ◽

Eukaryotic Species ◽

The Cross

Experimental studies of Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular and cellular processes in metazoans at large. Since the publication of their genomes, functional genomic investigations have identified genes that are essential or non-essential for survival in each species. Recently, a range of features linked to gene essentiality have been inferred using a machine learning (ML)-based approach, allowing essentiality predictions within a species. Nevertheless, predictions between species are still elusive. Here, we undertake a comprehensive study using ML to discover and validate features of essential genes common to both C. elegans and D. melanogaster. We demonstrate that the cross-species prediction of gene essentiality is possible using a subset of features linked to nucleotide/protein sequences, protein orthology and subcellular localisation, single-cell RNA-seq, and histone methylation markers. Complementary analyses showed that essential genes are enriched for transcription and translation functions and are preferentially located away from heterochromatin regions of C. elegans and D. melanogaster chromosomes. The present work should enable the cross-prediction of essential genes between model and non-model metazoans.

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Shotgun lipidomics of liver and brain tissue of Alzheimer’s disease model mice treated with acitretin

Scientific Reports ◽

10.1038/s41598-021-94706-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna A. Lauer ◽

Daniel Janitschke ◽

Malena dos Santos Guilherme ◽

Vu Thu Thuy Nguyen ◽

Cornel M. Bachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Lipid Homeostasis ◽

Medical Surveillance ◽

Shotgun Lipidomics ◽

App Processing ◽

Cognitive Improvement ◽

The Impact

AbstractAlzheimer’s disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-β (Aβ). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris, increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aβ-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients.

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