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Article ; Online: A Robust Assay to Monitor Ataxin-3 Amyloid Fibril Assembly

Francisco Figueiredo / Mónica Lopes-Marques / Bruno Almeida / Nena Matscheko / Pedro M. Martins / Alexandra Silva / Sandra Macedo-Ribeiro

Cells, Vol 11, Iss 1969, p

2022 Volume 1969

Abstract: Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a glutamine repeat in the protein ataxin-3, which is deposited as intracellular aggregates in affected brain regions. Despite the controversial role of ataxin-3 amyloid structures in SCA3 ...

Abstract	Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a glutamine repeat in the protein ataxin-3, which is deposited as intracellular aggregates in affected brain regions. Despite the controversial role of ataxin-3 amyloid structures in SCA3 pathology, the identification of molecules with the capacity to prevent aberrant self-assembly and stabilize functional conformation(s) of ataxin-3 is a key to the development of therapeutic solutions. Amyloid-specific kinetic assays are routinely used to measure rates of protein self-assembly in vitro and are employed during screening for fibrillation inhibitors. The high tendency of ataxin-3 to assemble into oligomeric structures implies that minor changes in experimental conditions can modify ataxin-3 amyloid assembly kinetics. Here, we determine the self-association rates of ataxin-3 and present a detailed study of the aggregation of normal and pathogenic ataxin-3, highlighting the experimental conditions that should be considered when implementing and validating ataxin-3 amyloid progress curves in different settings and in the presence of ataxin-3 interactors. This assay provides a unique and robust platform to screen for modulators of the first steps of ataxin-3 aggregation—a starting point for further studies with cell and animal models of SCA3.
Keywords	thioflavin-T ; polyglutamine expansion ; reproducibility ; ubiquitin ; self-association rates ; equilibrium dissociation constant ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Complex interactions between p.His558Arg and linked variants in the sodium voltage-gated channel alpha subunit 5 (NaV1.5)

Monica Lopes-Marques / Raquel Silva / Catarina Serrano / Verónica Gomes / Ana Cardoso / Maria João Prata / Antonio Amorim / Luisa Azevedo

PeerJ, Vol 10, p e

2022 Volume 13913

Abstract: Common genetic polymorphisms may modify the phenotypic outcome when co-occurring with a disease-causing variant, and therefore understanding their modulating role in health and disease is of great importance. The polymorphic p.His558Arg variant of the ... ...

Abstract	Common genetic polymorphisms may modify the phenotypic outcome when co-occurring with a disease-causing variant, and therefore understanding their modulating role in health and disease is of great importance. The polymorphic p.His558Arg variant of the sodium voltage-gated channel alpha subunit 5 (NaV1.5) encoded by the SCN5A gene is a case in point, as several studies have shown it can modify the clinical phenotype in a number of cardiac diseases. To evaluate the genetic backgrounds associated with this modulating effect, we reanalysed previous electrophysiological findings regarding the p.His558Arg variant and further assessed its patterns of genetic diversity in human populations. The NaV1.5 p.His558Arg variant was found to be in linkage disequilibrium with six other polymorphic variants that previously were also associated with cardiac traits in GWAS analyses. On account of this, incongruent reports that Arg558 allele can compensate, aggravate or have no effect on NaV1.5, likely might have arose due to a role of p.His558Arg depending on the additional linked variants. Altogether, these results indicate a major influence of the epistatic interactions between SCN5A variants, revealing also that phenotypic severity may depend on the polymorphic background associated to each individual genome.
Keywords	Sodium voltage-gated channel alpha subunit 5 (NaV1.5) ; SCN5A variants ; Genetic background ; Linkage disequilibrium ; Genetic modifier ; Epistasis ; Medicine ; R ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	PeerJ Inc.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Essential genetic findings in neurodevelopmental disorders

Ana R. Cardoso / Mónica Lopes-Marques / Raquel M. Silva / Catarina Serrano / António Amorim / Maria J. Prata / Luísa Azevedo

Human Genomics, Vol 13, Iss 1, Pp 1-

2019 Volume 7

Abstract: Abstract Neurodevelopmental disorders (NDDs) represent a growing medical challenge in modern societies. Ever-increasing sophisticated diagnostic tools have been continuously revealing a remarkably complex architecture that embraces genetic mutations of ... ...

Abstract	Abstract Neurodevelopmental disorders (NDDs) represent a growing medical challenge in modern societies. Ever-increasing sophisticated diagnostic tools have been continuously revealing a remarkably complex architecture that embraces genetic mutations of distinct types (chromosomal rearrangements, copy number variants, small indels, and nucleotide substitutions) with distinct frequencies in the population (common, rare, de novo). Such a network of interacting players creates difficulties in establishing rigorous genotype-phenotype correlations. Furthermore, individual lifestyles may also contribute to the severity of the symptoms fueling a large spectrum of gene-environment interactions that have a key role on the relationships between genotypes and phenotypes. Herein, a review of the genetic discoveries related to NDDs is presented with the aim to provide useful general information for the medical community.
Keywords	Neurodevelopmental disorders ; Brain-related genes ; Deleterious mutations ; de novo mutations ; Polymorphisms ; Risk alleles ; Medicine ; R ; Genetics ; QH426-470
Subject code	616
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of a Novel Nucleobase-Ascorbate Transporter Family Member in Fish and Amphibians

Diogo Oliveira / André M. Machado / Tiago Cardoso / Mónica Lopes-Marques / L. Filipe C. Castro / Raquel Ruivo

Fishes, Vol 4, Iss 1, Pp 1-

2019

Abstract: Nucleobase-Ascorbate Transporter (NAT) family includes ascorbic acid, nucleobases, and uric acid transporters: With broad evolutionary distribution. In vertebrates, four members have been previously recognized, the ascorbate transporters Slc23a1 and ... ...

Abstract	Nucleobase-Ascorbate Transporter (NAT) family includes ascorbic acid, nucleobases, and uric acid transporters: With broad evolutionary distribution. In vertebrates, four members have been previously recognized, the ascorbate transporters Slc23a1 and Slc3a2, the nucleobase transporter Slc23a4 and an orphan transporter Slc23a3. Using phylogenetic and synteny analysis, we identify a fifth member of the vertebrate slc23 complement (slc23a5), present in neopterygians (gars and teleosts) and amphibians, and clarify the evolutionary relationships between the novel gene and known slc23 genes. Further comparative analysis puts forward uric acid as the preferred substrate for Slc23a5. Gene expression quantification, using available transcriptomic data, suggests kidney and testis as major expression sites in Xenopus tropicalis (western clawed frog) and Danio rerio (zebrafish). Additional expression in brain was detected in D. rerio, while in the Neoteleostei Oryzias latipes (medaka) slc23a5 expression is restricted to the brain. The biological relevance of the retention of an extra transporter in fish and amphibians is discussed.
Keywords	Nucleobase-Ascorbate Transporters (NAT) ; Slc23 ; Slc23a5 ; uric acid ; antioxidant ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SLC35A2-CDG

Dulce Quelhas / Joana Correia / Jaak Jaeken / Luísa Azevedo / Mónica Lopes-Marques / Anabela Bandeira / Liesbeth Keldermans / Gert Matthijs / Luisa Sturiale / Esmeralda Martins

Molecular Genetics and Metabolism Reports, Vol 26, Iss , Pp 100717- (2021)

Novel variant and review

2021

Abstract: SLC35A2 encodes the X-linked transporter that carries uridine diphosphate (UDP)-galactose from the cytosol to the lumen of the Golgi apparatus and the endoplasmic reticulum. Pathogenic variants have been associated to a congenital disorder of ... ...

Abstract	SLC35A2 encodes the X-linked transporter that carries uridine diphosphate (UDP)-galactose from the cytosol to the lumen of the Golgi apparatus and the endoplasmic reticulum. Pathogenic variants have been associated to a congenital disorder of glycosylation (CDG) with epileptic encephalopathy as a predominant feature. Among the sixty five patients described so far, a strong gender bias is observed as only seven patients are males. This work is a review and reports a SLC35A2-CDG in a male without epilepsy and with growth deficiency associated with decreased serum IGF1, minor neurological involvement, minor facial dysmorphism, and camptodactyly of fingers and toes. Sequence analysis revealed a hemizygosity for a novel de novo variant: c.233A > G (p.Lys78Arg) in SLC35A2. Further analysis of SLC35A2 sequence by comparing both orthologous and paralogous positions, revealed that not only the variant found in this study, but also most of the reported mutated positions are conserved in SLC35A2 orthologous, and many even in the paralogous SLC35A1 and SLC35A3. This is strong evidence that replacements at these positions will have a critical pathological effect and may also explain the gender bias observed among SLC35A2-CDG patients.
Keywords	CDG ; Congenital disorder(s) of glycosylation ; IGF1 ; Phenotype ; SLC35A2 ; Variant ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Losing Genes

Gonçalo Espregueira Themudo / Luís Q. Alves / André M. Machado / Mónica Lopes-Marques / Rute R. da Fonseca / Miguel Fonseca / Raquel Ruivo / L. Filipe C. Castro

Frontiers in Marine Science, Vol

The Evolutionary Remodeling of Cetacea Skin

2020 Volume 7

Abstract: The skin is a multi-layered organ, often displaying associated structures, that establishes a protective interface between the organism and the surrounding environment. In mammals, the skin provides a physical and immune barrier, while contributing to ... ...

Abstract	The skin is a multi-layered organ, often displaying associated structures, that establishes a protective interface between the organism and the surrounding environment. In mammals, the skin provides a physical and immune barrier, while contributing to thermoregulation and water balance. Within cetaceans, the archetypal mammalian skin was drastically reshaped and remodeled, emerging as a striking feature of their successful adaptation to a fully aquatic lifestyle. In fact, cetacean skin is extremely thick, displays a high cellular turnover rate, and lacks typical mammalian pelages, as well as sebaceous glands, resulting in a smooth and drag-reducing skin. Curiously, at the genome level, the majority of cetacean skin-related innovations resulted from episodes of gene loss: spanning diverse processes such as skin keratinization and cornification, immunity and inflammation or lubrication. Here, we review how the cetacean skin was shaped by such an evolutionary mechanism, by describing the full set of genes with inactivating mutations in the various functional compartments of the skin.
Keywords	gene loss ; cetacean ; skin ; genome ; lossOme ; Science ; Q ; General. Including nature conservation ; geographical distribution ; QH1-199.5
Subject code	571
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: A complete enzymatic capacity for long-chain polyunsaturated fatty acid biosynthesis is present in the Amazonian teleost tambaqui, Colossoma macropomum

Ferraz, Renato B / Naoki Kabeya / Mónica Lopes-Marques / André M. Machado / Ricardo A. Ribeiro / Ana L. Salaro / Rodrigo Ozório / L. Filipe C. Castro / Óscar Monroig

Comparative biochemistry and physiology. 2019 Jan., v. 227

2019

Abstract: In vertebrates, the essential fatty acids (FA) that satisfy the dietary requirements for a given species depend upon its desaturation and elongation capabilities to convert the C18 polyunsaturated fatty acids (PUFA), namely linoleic acid (LA, 18:2n-6) ... ...

Abstract	In vertebrates, the essential fatty acids (FA) that satisfy the dietary requirements for a given species depend upon its desaturation and elongation capabilities to convert the C18 polyunsaturated fatty acids (PUFA), namely linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n–3), into the biologically active long-chain (C20–24) polyunsaturated fatty acids (LC-PUFA), including arachidonic acid (ARA, 20:4n-6), eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Recent studies have established that tambaqui (Colossoma macropomum), an important aquaculture-produced species in Brazil, is a herbivorous fish that can fulfil its essential FA requirements with dietary provision C18 PUFA LA and ALA, although the molecular mechanisms underpinning such ability remained unclear. The present study aimed at cloning and functionally characterizing genes encoding key desaturase and elongase enzymes, namely fads2, elovl5 and elovl2, involved in the LC-PUFA biosynthetic pathways in tambaqui. First, a fads2-like desaturase was isolated from tambaqui. When expressed in yeast, the tambaqui Fads2 showed Δ6, Δ5 and Δ8 desaturase capacities within the same enzyme, enabling all desaturation reactions required for ARA, EPA and DHA biosynthesis. Moreover, tambaqui possesses two elongases that are bona fide orthologs of elovl5 and elovl2. Their functional characterization confirmed that they can operate towards a variety of PUFA substrates with chain lengths ranging from 18 to 22 carbons. Overall our results provide compelling evidence that demonstrates that all the desaturase and elongase activities required to convert LA and ALA into ARA, EPA and DHA are present in tambaqui within the three genes studied herein, i.e. fads2, elovl5 and elovl2.
Keywords	Colossoma macropomum ; alpha-linolenic acid ; arachidonic acid ; biochemical pathways ; biosynthesis ; docosahexaenoic acid ; eicosapentaenoic acid ; enzyme activity ; genes ; herbivorous fish ; linoleic acid ; long chain polyunsaturated fatty acids ; nutrient requirements ; stearoyl-CoA desaturase ; yeasts ; Brazil
Language	English
Dates of publication	2019-01
Size	p. 90-97.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	121247-3
ISSN	1879-1107 ; 0305-0491 ; 1096-4959
ISSN (online)	1879-1107
ISSN	0305-0491 ; 1096-4959
DOI	10.1016/j.cbpb.2018.09.003
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The evolution of pepsinogen C genes in vertebrates

Luís Filipe Costa Castro / Monica Lopes-Marques / Odete Gonçalves / Jonathan Mark Wilson

PLoS ONE, Vol 7, Iss 3, p e

duplication, loss and functional diversification.

2012 Volume 32852

Abstract: Background Aspartic proteases comprise a large group of enzymes involved in peptide proteolysis. This collection includes prominent enzymes globally categorized as pepsins, which are derived from pepsinogen precursors. Pepsins are involved in gastric ... ...

Abstract	Background Aspartic proteases comprise a large group of enzymes involved in peptide proteolysis. This collection includes prominent enzymes globally categorized as pepsins, which are derived from pepsinogen precursors. Pepsins are involved in gastric digestion, a hallmark of vertebrate physiology. An important member among the pepsinogens is pepsinogen C (Pgc). A particular aspect of Pgc is its apparent single copy status, which contrasts with the numerous gene copies found for example in pepsinogen A (Pga). Although gene sequences with similarity to Pgc have been described in some vertebrate groups, no exhaustive evolutionary framework has been considered so far. Methodology/principal findings By combining phylogenetics and genomic analysis, we find an unexpected Pgc diversity in the vertebrate sub-phylum. We were able to reconstruct gene duplication timings relative to the divergence of major vertebrate clades. Before tetrapod divergence, a single Pgc gene tandemly expanded to produce two gene lineages (Pgbc and Pgc2). These have been differentially retained in various classes. Accordingly, we find Pgc2 in sauropsids, amphibians and marsupials, but not in eutherian mammals. Pgbc was retained in amphibians, but duplicated in the ancestor of amniotes giving rise to Pgb and Pgc1. The latter was retained in mammals and probably in reptiles and marsupials but not in birds. Pgb was kept in all of the amniote clade with independent episodes of loss in some mammalian species. Lineage specific expansions of Pgc2 and Pgbc have also occurred in marsupials and amphibians respectively. We find that teleost and tetrapod Pgc genes reside in distinct genomic regions hinting at a possible translocation. Conclusions We conclude that the repertoire of Pgc genes is larger than previously reported, and that tandem duplications have modelled the history of Pgc genes. We hypothesize that gene expansion lead to functional divergence in tetrapods, coincident with the invasion of terrestrial habitats.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Consequences of primer binding-sites polymorphisms on genotyping practice

Estefânia M. Martins / Laura Vilarinho / Sofia Esteves / Mónica Lopes-Marques / António Amorim / Luísa Azevedo

Open Journal of Genetics , Vol 01, Iss 02, Pp 15-

2011 Volume 17

Abstract: Herein we investigated the effect of primer binding site polymorphisms in achieving correct genotyping when a mismatch occurs in distinct positions of the primer sequence. For that purpose primer sequences were designed in order to carry either allelic ... ...

Abstract	Herein we investigated the effect of primer binding site polymorphisms in achieving correct genotyping when a mismatch occurs in distinct positions of the primer sequence. For that purpose primer sequences were designed in order to carry either allelic form at the 3’ end and at 3 bp, 5 bp and 7 bp apart from the 3’ end of an intronic polymorphism (rs2247836) observed in phenylalanine hydroxylase ( PAH ) gene. For one of the alleles annealing failure was obtained when the mismatch occurs at all the four primer-site locations. Primer sequences carrying the alternative SNP allele resulted to be less specific as the distance to the primer-3’ end was increased. Altogether, these results revealthat effects in the extension of the annealing failure is allele and mismatch-position dependent.
Keywords	Primer Binding-site ; SNP ; < ; i> ; PAH< ; /i> ; Gene ; Molecular Genetics ; Genetics ; QH426-470 ; Biology (General) ; QH301-705.5 ; Science ; Q ; DOAJ:Genetics ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
Subject code	501
Language	English
Publishing date	2011-09-01T00:00:00Z
Publisher	Scientific Research Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Statins: An undesirable class of aquatic contaminants?

Santos, Miguel M / Carmen B. de los Santos / L. Filipe C. Castro / Mónica Lopes-Marques / Raquel Ruivo / Teresa Neuparth / Tiago Torres

Aquatic toxicology. 2016 May, v. 174

2016

Abstract: Emerging pollutants, such as pharmaceuticals, may pose a considerable environment risk. Hypocholesterolaemic drugs such as statins are among the most prescribed human pharmaceuticals in western European countries. In vertebrates, this therapeutic class ... ...

Abstract	Emerging pollutants, such as pharmaceuticals, may pose a considerable environment risk. Hypocholesterolaemic drugs such as statins are among the most prescribed human pharmaceuticals in western European countries. In vertebrates, this therapeutic class disrupts the cholesterol synthesis by inhibiting the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), responsible for the limiting step in the mevalonate pathway. Recently, functional studies have shown that statins competitively inhibit HMGR in vertebrates and arthropods, two taxa that have diverged over 450 million years ago. Importantly, chronic simvastatin exposure disrupts crustacean reproduction and development at environmentally relevant concentrations. Hence, a fundamental question emerges: what is the taxonomic scope of statins-induced HMGR inhibition across metazoans? Here, we address this central question in a large sampling of metazoans using comparative genomics, homology modelling and molecular docking. Sequence alignment of metazoan HMGRs allowed the annotation of highly conserved catalytic, co-factor and substrate binding sites, including residues highjacked for statin binding. Furthermore, molecular docking shows that the catalytic domains of metazoan HMGRs are highly conserved regarding interactions, not only with HMG-CoA, but also with both simvastatin and atorvastatin, the top prescribed statins in Europe and USA. Hence, the data indicates that both statins are expected to competitively inhibit metazoan's HMGRs, and therefore all metazoan taxa might be at risk. The environmental relevance of these findings are discussed and research priorities established. We believe that the conceptual framework used in this study can be applied to other emerging pollutants and assist in the design of toxicity testing and risk assessment.
Keywords	active sites ; arthropods ; binding sites ; cholesterol ; Crustacea ; drugs ; genomics ; humans ; molecular models ; pollutants ; reproduction ; risk ; risk assessment ; sequence alignment ; toxicity testing ; Europe ; United States ; Western European region
Language	English
Dates of publication	2016-05
Size	p. 1-9.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	782699-0
ISSN	1879-1514 ; 0166-445X
ISSN (online)	1879-1514
ISSN	0166-445X
DOI	10.1016/j.aquatox.2016.02.001
Database	NAL-Catalogue (AGRICOLA)

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