Un equip internacional liderat per investigadors de l’IRTA a l’IBB-UAB identifica els gens que permeten als peixos teleostis marins hidratar els ous perquè surin i es dispersin, i aconsegueixin així sobreviure. Els mecanismes identificats aporten nova informació sobre l’evolució dels teleostis, grup al qual pertany gairebé el total dels peixos marins actuals, els avantpassats dels quals es van aventurar a passar de l’aigua dolça al domini salí.

Investigadors d’Espanya, Itàlia i Noruega aporten nous coneixements sobre com la majoria dels teleostis, que conformen el 96 % dels peixos marins actuals, van desenvolupar mecanismes d’hidratació que fan que els seus ous surin i es dispersin als oceans, en un nou estudi publicat a la revista Molecular Biology and Evolution. Els científics han descobert un grup de gens de canals d’aigua que només existeix en els teleostis. Aquests gens permeten que l’aigua flueixi a través de les membranes cel·lulars i s’expressin específicament en les membranes externes de l’ou durant la maduració.

L’estudi ha estat liderat per Joan Cerdà i Roderick Nigel Finn, investigadors de l’Institut de Recerca i Tecnologia Agroalimentàries (IRTA) i de la Universitat de Bergen (Noruega), adscrits a l’Institut de Biotecnologia i Biomedicina de la Universitat Autònoma de Barcelona (IBB-UAB). Hi han participat també investigadors de l’Institut de Ciències del Mar (ICM-CSIC), el Centre de Regulació Genòmica de Barcelona (CRG), l’Institut de Recerca Marina de Noruega (IMR) i la Universitat de Pàdua (Itàlia).

Tot i que els peixos han nedat al mar des de fa centenars de milions d’anys, no sempre ha estat així. Es considera que els seus avantpassats van evolucionar en aigua dolça. Això va suposar un gran problema fisiològic per als pioners i els seus seguidors que es van aventurar en el domini salí, ja que la concentració de sal dels seus fluids corporals era, com en els humans, molt inferior a la de l’aigua de mar. Tots els teleostis moderns reflecteixen aquesta condició i, tal com els seus avantpassats, s’enfronten a la deshidratació a causa del moviment passiu de l’aigua del seu cos cap al medi extern amb alt contingut en sal. A diferència dels humans, que no podem beure aigua de mar per la incapacitat dels nostres ronyons per eliminar l’excés de sal, els teleostis marins van desenvolupar aquesta capacitat utilitzant cèl·lules especialitzades a les brànquies. No obstant això, hi havia una important excepció. Per conquerir plenament un medi, és necessari reproduir-s’hi, però els ous unicel·lulars dels teleostis no tenen cap dels sistemes orgànics dels individus juvenils i adults i no poden beure aigua de mar. La solució adaptativa desenvolupada pels teleostis marins consisteix en el fet que hidraten els seus ous en maduració abans que siguin ovulats per proporcionar-los l’aigua necessària perquè es desenvolupin els embrions. Aquesta acumulació d’aigua determina si els ous alliberats són més pesats o lleugers que l’aigua de mar circumdant i, per tant, si s’enfonsaran en el fons marí o suraran i es dispersaran en els oceans.

Gens duplicats amb la mateixa funció

Un aspecte inusual dels gens que han identificat els investigadors és que són duplicats estretament relacionats que fan la mateixa funció. Normalment, quan sorgeixen duplicats de gens estretament relacionats, un d’ells pot adquirir una nova funció o es perd a causa de la seva redundància funcional. «En aquest cas, els nous gens conserven la mateixa funció en la mateixa membrana dels ous», assenyala Joan Cerdà.

Mitjançant el cribratge de centenars de genomes de teleostis, l’estudi revela que pràcticament totes les espècies que produeixen exclusivament ous flotants conserven almenys un dels gens, i un terç d’elles conserven tots dos gens. En canvi, gairebé la meitat de les espècies que produeixen ous que no suren en aigua de mar han perdut tots dos gens, i gairebé totes les espècies que incuben els seus ous internament, com els cavallets marins, també han perdut tots dos gens.

Per descobrir com els ous flotants utilitzen els gens, els investigadors han emprat una àmplia varietat de tècniques experimentals unides a les tecnologies més avançades de seqüenciació de l’ADN per demostrar que les proteïnes resultants de cada gen han desenvolupat mecanismes evolutius específics que controlen la seva inserció en les membranes externes dels ous. «Quan aquests mecanismes s’activen, cada canal s’uneix a una mena de proteïna fins ara desconeguda que manté els canals en la membrana», detalla Roderick Nigel Finn. Aquestes noves proteïnes descobertes pels investigadors només es troben en peixos teleostis.

Una característica que ha sorprès els investigadors és que un segon mecanisme d’activació fa que un dels canals es desplaci a una part diferent de la membrana externa de l’ou. D’aquesta manera, tots dos canals continuen exercint la mateixa funció i eviten competir pel mateix espai en la membrana. El resultat és que s’accelera el flux d’aigua cap a l’interior de l’ou en maduració. El procés finalitza quan s’alliberen les noves proteïnes d’unió, la qual cosa provoca que els dos canals abandonin la membrana externa de l’ou i l’aigua adquirida a l’interior de l’ou quedi retinguda.

El mecanisme d’hidratació és tan eficaç que dota als ous de més d’un 90 % d’aigua. Quan, un cop alliberats al medi marí, són fecundats, els ous suren com passatgers passius en els corrents oceànics i són transportats a nous horitzons.

Article: Alba Ferré, François Chauvigné, Anna Vlasova, Birgitta Norberg, Luca Bargelloni, Roderic Guigó, Roderick Nigel Finn, Joan Cerdà, Functional evolution of clustered aquaporin genes reveals insights into the oceanic success of teleost eggs, Molecular Biology and Evolution, 2023; msad071, https://doi.org/10.1093/molbev/msad071

During meiotic prophase I, tightly regulated processes take place, from pairing and synapsis of homologous chromosomes to recombination, which are essential for the generation of genetically variable haploid gametes. These processes have canonical meiotic features conserved across different phylogenetic groups. However, the dynamics of meiotic prophase I in non-mammalian vertebrates are poorly known. Here, we compare four species from Sauropsida to understand the regulation of meiotic prophase I in reptiles: the Australian central bearded dragon (Pogona vitticeps), two geckos (Paroedura picta and Coleonyx variegatus) and the painted turtle (Chrysemys picta). We first performed a histological characterization of the spermatogenesis process in both the bearded dragon and the painted turtle. We then analyzed prophase I dynamics, including chromosome pairing, synapsis and the formation of double strand breaks (DSBs). We show that meiosis progression is highly conserved in reptiles with telomeres clustering forming the bouquet, which we propose promotes homologous pairing and synapsis, along with facilitating the early pairing of micro-chromosomes during prophase I (i.e., early zygotene). Moreover, we detected low levels of meiotic DSB formation in all taxa. Our results provide new insights into reptile meiosis.

Citation: Marín-Gual L, González-Rodelas L, M. Garcias M, Kratochvíl L, Valenzuela N, Georges A, Waters PD and Ruiz-Herrera A (2022) Meiotic chromosome dynamics and double strand break formation in reptiles. Front. Cell Dev. Biol. 10:1009776. doi: 10.3389/fcell.2022.1009776

Amb el títol “Societat i universitat: juntes, més lluny”, la quarta edició de la Nit del Consell Social pretén generar un espai de diàleg i debat sobre com es poden estrènyer i millorar els lligams entre la societat i la universitat.

El Premi Transferència UAB del Consell Social de la UAB el recollirà l’investigador de l’Institut de Biotecnologia i de Biomedicina de la UAB, Salvador Ventura, per la seva trajectòria de recerca i transferència en el camp de la Bioquímica i la Biologia Molecular i, concretament, en l’estudi multidisciplinar del plegament de proteïnes i de com la pèrdua de la seva funcionalitat i el procés d’agregació conseqüent estan en l’origen de nombroses patologies, incloent-hi diverses de caràcter degeneratiu com el Parkinson.

Des de l’IBB ens enorgulleix que un dels nostres investigadors hagi estat distingit amb aquest premi i us animem a formar part de l’acte que es realitzarà al plató de televisió de la Facultat de Comunicació de la UAB i que també es podrà seguir en streaming a través del canal de Youtube de la UAB.

L’aforament a l’acte és limitat. Les persones interessades en assistir-hi poden inscriure’s a través del següent enllaç.

• Open position at Joan Cerdà Research Group to apply for Beatriu de Pinós postdoctoral grant.

An IBB project led by Salvador Ventura has been one of six selected by the Multiple System Atrophy Coalition in its research grant programme. The grant will allow researchers to advance in the study of molecules they have identified as being potential candidates for a treatment of multiple system atrophy. This neurodegenerative disease affects more than 30,000 people in Europe. 

The Protein Folding and Conformational Diseases research group at the Institute of Biotechnology and Biomedicine (IBB), led by Salvador Ventura, professor of the Department of Biochemistry and Molecular Biology, has won one of the grants awarded annually by the Multiple System Atrophy Coalition, a prestigious international non-profit organisation that aims to improve the quality of life of people with multiple system atrophy (MSA), which affects more than 30,000 people in Europe alone.  

MSA is a rapidly progressive and highly disabling disease that belongs to the group of synucleinopathies (which also includes Parkinson’s disease). It is caused by the accumulation in the brain of a protein, alpha-synuclein, which forms toxic aggregates due to poor folding, leading to glial and neuronal dysfunction and neurodegeneration.  

The IBB researchers’ project, entitled “Optimization of a small molecule to inhibit alpha-synuclein aggregation in MSA”, has been awarded a budget of €50,000. This will allow researchers to evaluate the anti-aggregation, neuroprotective activity and pharmacokinetic properties of some thirty second-generation molecules identified in previous studies and which have high theoretical permeability to the blood-brain barrier and anti-aggregation activity. The molecules will be evaluated in vitro and the most active compounds will be studied in two C. Elegans models of the disease. In a second phase of the project, which can be renewed for another year, the researchers will test the two best molecules in mouse models of MSA. This second part of the project has also been awarded a Proof of Concept grant from the UAB and will be carried out in collaboration with Professor Wassilios Meissner, director of the Institute of Neurodegenerative Diseases at the University of Bordeaux.  “So far, no treatment has been discovered that can modify the course of MSA and current drugs provide only partial relief. It is therefore urgent to develop treatments to slow its progression,” explains Salvador Ventura. The researcher says his team’s ultimate goal is to validate a molecule with optimal drug-like properties and the ability to reduce alpha-synuclein aggregation and neuronal loss in mice, in order to generate the preclinical basis for a future therapy. 

In March of 2020, thousands of scientists around the world united to answer a pressing and complex question: what genetic factors influence why some COVID-19 patients develop severe, life-threatening disease requiring hospitalization, while others escape with mild symptoms or none at all?

This global effort, called the COVID-19 Host Genetics Initiative, was founded in March 2020 by Andrea Ganna, group leader at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki and Mark Daly, director of FIMM and institute member at the Broad Institute of MIT and Harvard. The initiative has grown to be one of the most extensive collaborations in human genetics and currently includes more than 3,300 authors and 61 studies from 25 countries and The IBB researcher Mario Cáceres, group leader of the Comparative and Functional Genomics Group, was one of the scientists that were involved within the initiative.

A comprehensive summary of their findings to date, published in Nature, reveals 13 loci, or locations in the human genome, that are strongly associated with infection or severe COVID-19. To do their analysis, the consortium pooled clinical and genetic data from the nearly 50,000 patients in their study who tested positive for the virus, and 2 million controls across numerous biobanks, clinical studies, and direct-to-consumer genetic companies such as 23andMe. Because of the large amount of data pouring, thanks to collaborative efforts and a cohesive spirit of data-sharing and transparency from around the world, the scientists were able to produce statistically robust analyses far more quickly, and from a greater diversity of populations, than any one group could have on its own.

Of the 13 loci identified so far by the team, two had higher frequencies among patients of East Asian or South Asian ancestry than in those of European ancestry, underscoring the importance of diversity in genetic datasets.

The team highlighted one of these two loci in particular, near the FOXP4 gene, which is linked to lung cancer. The FOXP4 variant associated with severe COVID-19 increases the gene’s expression, suggesting that inhibiting the gene could be a potential therapeutic strategy. Other loci associated with severe COVID-19 included DPP9, a gene also involved in lung cancer and pulmonary fibrosis, and TYK2, which is implicated in some autoimmune diseases.

The researchers also identified causal factors such as smoking and high body mass index.

The findings could help provide targets for future therapies, including the use of repurposed drugs, and illustrate the power of genetic studies in learning more about infectious disease. An improvement in COVID-19 treatment, which can be informed by genetic analysis, can shift the pandemic to an endemic disease that is more localized and present at low but consistent levels in the population, much like the flu. This will considerably decrease the burden to the health system and the impact on country’s economy.

The COVID-19 Host Genetics Initiative. Mapping the human genetic architecture of COVID-19. Nature. Online July 8, 2021. https://www.nature.com/articles/s41586-021-03767-x

Researchers at the UAB and the UniZar have identified a human peptide found in the brain that blocks the α-synuclein aggregates involved in Parkinson’s disease and prevents their neurotoxicity. The study, published in Nature Communications, suggests that this could be one of the organism’s natural mechanisms with which to fight aggregation. The discovery may help to develop new therapeutic and diagnosis strategies for Parkinson’s disease and other synuclein pathologies.

The death of neurons specialised in the synthesis of dopamine, one of the brain’s main neurotransmissors, deteriorates the motor and cognitive capacities of those with Parkinson’s disease. The loss of these neurons is related to alpha-synuclein aggregation. Recent studies show that oligomers, the initial aggregates of this protein, are the most pathogenic forms of α-synuclein and are responsible for the spreading of the disease in the brain.

Therefore, one of the more promising approaches in fighting this disorder consists in neutralising these oligomers and, thus, slow down the pathological progression. However, the fact that these aggregates do not present a defined structure and that they are transitory by nature makes it extremely difficult to identify molecules that bind with enough strength as to explore any clinical application.

A scientific collaboration between researchers from the Institute for Biotechnology and Biomedicine (IBB) at the Universitat Autònoma de Barcelona (UAB) and from the Instituto de Biocomputación y Física de Sistemas Complejos (BIFI) of the Universidad de Zaragoza (UniZar) now has been able to identify a human endogenous peptide which strongly and specifically attaches to the α-synuclein oligomers, thus avoiding their aggregation and blocking their neurotoxicity, two processes closely related to the neurodegenerative decline of Parkinson’s disease. The identification and study of the peptide, called LL-37, was recently published in Nature Communications.

“LL-37 interacts with the toxic alpha-synuclein oligomers in a selective manner and with a strength superior to that of any peptide previously described, equivalent to the strength exhibited by antibodies. It inhibits aggregation at very low concentrations and protects neuronal cells from being damaged”, researchers point out.

They add that, “LL-37 is found naturally in the human organism, both in the brain and in the intestine, organs in which α-synuclein aggregation takes place in Parkinson’s disease. This suggests that LL-37’s activity might respond to a mechanism developed by the body itself as a means to naturally fight this disease.”

Encouraged by this idea, researchers now want to study how its expression can be regulated and if this strategy can become a safe therapy with the potential of influencing the course of the disease. “There is a possibility that a therapy for Parkinson’s disease already lies in our interior and that it only needs to be activated correctly”, states Salvador Ventura, researcher at the IBB and coordinator of the study.

The identification of LL-37 was conducted under the framework of a research analysing the structure and characteristics of pathogenic oligomers with the aim of neutralising them in a specific manner. The analyses conducted demonstrate that helical peptides with a hydrophobic side and another positively charged side are ideal for this type of activity. The trials allowed researchers to identify three molecules with anti-aggregation activity: in addition to the human molecule, a second peptide present in bacteria and a third artificially made molecule were identified.

In addition to representing a possible therapeutic route for Parkinson’s disease and other synuclein pathologies, the molecules identified in the study are promising tools for its diagnosis, given that they discriminate between functional and toxic α-synuclein species.

“Until now there were no molecules capable of selectively and efficiently identifying toxic α-synuclein aggregates; the peptides we present on these issues are unique and, therefore, have great potential as diagnostic and prognostic tools,” says study co-coordinator Nunilo Cremades, researcher at BIFI-UniZar.

In the study, over 25,000 human peptides were computationally analysed, and single molecule spectroscopy methods, as well as protein engineering, were applied, in addition to cell cultures in vitro using toxic oligomers.

Participating in the study were researchers from the IBB-UAB and the Department of Biochemistry and Molecular Biology at the UAB Jaime Santos (first author of the article), Irantzu Pallarès and Salvador Ventura (co-coordinators of the study), members of the “Protein Folding and Conformational Diseases” group; and BIFI-UniZar researchers Pablo Gracia (second author of the article) and Nunilo Cremades (co-coordinator of the study, predoctoral researcher and lead researcher, respectively, of the “Amyloid Protein Misfolding and Aggregation” NEUROMOL group from the BIFI-Unizar.

Original article: Santos, J., Gracia, P., Navarro, S. et al. α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity. Nat Commun 12, 3752 (2021). https://doi.org/10.1038/s41467-021-24039-2