Artículos (Bioquímica y Biología Molecular)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/10995

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Ulcerative colitis model triggers gut α-Synuclein aggregation without brain involvement or neuronal loss in female rats
(Frontiers Media SA, 2026) Espinosa Oliva, Ana María; Vázquez Carretero, María Dolores; Ruiz Laza, Rocío; Roca-Ceballos, María A.; García Miranda, Pablo; Peral Rubio, María José; Sarmiento Soto, Manuel; Herrera Carmona, Antonio José; Venero Recio, José Luis; Martínez de Pablos, Rocío; Bioquímica y Biología Molecular; Fisiología; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; European Union (UE)
Introduction: Despite being the second most common neurodegenerative disorder, the mechanisms underlying the onset and progression of Parkinson’s disease (PD) remain poorly understood, and no curative treatment is currently available. The Braak hypothesis offers an intriguing framework for explaining both the origin and development of the disease, proposing that PD begins in the gut and subsequently spreads to the brain. Methods: In previous studies, our group developed a novel PD model in which peripheral inflammation, triggered by administering dextran sodium sulphate (DSS) in the drinking water of male Wistar rats, recapitulates key features of PD in both the gut and the brain. This model supports the Braak hypothesis and highlights the relevance of the gut-brain axis. Using the same model, the present study aimed to determine whether sex influences peripheral inflammation and the resulting neuropathology in the substantia nigra (SN) of female Wistar rats. Results: Our findings show that while DSS treatment induces comparable levels of colonic inflammation and phosphorylated a-synuclein accumulation in both sexes, it does not produce a-synuclein aggregation or dopaminergic neuronal loss in the SN pars compacta of female rats. Conclusion: These results underscore the critical importance of considering sex differences in experimental PD models and in clinical practice, as such differences may significantly influence PD pathogenesis.
A novel sequential biphasic bioprocess (enzymatic/fermentative) for the valorisation of orange peel waste into products with potential biostimulant and biofertilizer activity
(Springer Heidelberg, 2026) Pina-Martín, Susana; Naranjo Fernández, Emilia; Orts Gómez, José María; Castaño Navarro, Angélica; Parrado Rubio, Juan; Bioquímica y Biología Molecular; Universidad de Sevilla
The orange juice manufacturing industry generates significant amounts of waste, consisting of peels, seeds, and pulp, which can pose environmental challenges if not properly managed. This study presents a novel two-phase bioprocess that combines enzymatic hydrolysis and bacterial fermentation. The process was developed to convert citrus waste (CW) into high-value products, achieving complete transformation into agronomic biostimulants and biofertilizers. The first phase involves enzymatic hydrolysis, which breaks down the biopolymeric components of CW—typically of low bioavailability—into simple sugars, peptides, and other metabolites with plant biostimulant properties. The second phase focusses on bacterial fermentation using strains naturally adapted to citrus waste, specifically Bacillus subtilis, which exhibits biofertilizer activities such as nitrogen fixation, phytohormone production, and siderophore secretion. The hydrolysed citrus waste served as the fermentation medium for B. subtilis. This bioprocess effectively manages CW by converting it entirely into biostimulant metabolites while generating biomass with biofertilizing functional activity. Beyond providing an environmentally sustainable solution for managing agricultural by-products, it demonstrates the potential of transforming waste into valuable agricultural resources. This approach creates a closed-loop system in line with the principles of the circular economy and offers new opportunities to advance sustainability and efficient resource management in the agricultural sector.
A novel biostimulant obtained from red wine lees enhances tolerance to ozone-induced abiotic stress in grapevine plants
(Frontiers Media SA, 2026) Naranjo Fernández, Emilia; Orts, Ángel; Orts Gómez, José María; Martín Presas, Luis; Castaño Navarro, Angélica; Parrado Rubio, Juan; Bioquímica y Biología Molecular; Ministerio de Ciencia e Innovación
The main objective of this study was to investigate the ability of a novel plant biostimulant obtained from red wine lees by enzymatic hydrolysis (LEE) to protect against abiotic ozone damage in grapevine plants (Vitis vinifera). Tropospheric ozone at high concentrations is considered a pollutant that harms plants by entering through the leaves via the stomata. Once inside, it decomposes into reactive oxygen species (ROS), causing oxidative stress, reduced photosynthesis, growth alterations, and visible symptoms such as necrotic spots and yellowing. LEE counteracted ozone-induced damage, as evidenced by net photosynthetic rate, electron transport rate, effective quantum yield of Photosystem II, and delayed fluorescence. LEE triggered the overexpression of genes involved in the synthesis of secondary metabolites that reduce oxidative damage and enhance resilience. Additionally, it decreases energy expenditure on emergency responses, as shown by the lower expression of stress-related genes. Consequently, the biostimulant optimizes metabolic efficiency and plant health
Isolation, Identification, and Characterization of Novel Environmental Bacteria with Polyurethane-Degrading Activity
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-09-22) Muñoz-Marti, Marta; Navarro Bañón, Virtudes; García-Poyo, M. Carmen; Castaño Forte, Carlos; Garrido, Josefina; Orts Gómez, José María; Huguet, Andrea; Garcia-Hernández, Jorge; Castillo, María Ángeles; Bioquímica y Biología Molecular; Centre for the Development of Industrial Technology (CDTI); Agencia Estatal de Investigación. España
Polyurethane (PU) is a widely used plastic material whose persistence in the environment entails a serious ecological challenge. This study aimed to isolate and characterize environmental bacteria capable of degrading PU, using Impranil DLN as a model substrate, and to investigate their enzymatic mechanisms and phylogenetic relationships. A total of 31 bacterial isolates were obtained from four waste accumulation sites and taxonomically identified across 12 different genera using MALDI-TOF MS and 16S rRNA gene sequencing. This analysis revealed genera not previously reported as PU biodegraders, including Priesta, Dermacoccus, Gordonia, Micrococcus, Pseudarthrobacter, and Agromyces. The Bacillus cereus clade was the most prevalent group, followed by the Priestia megaterium clade and Achromobacter sp. Biodegradation assays revealed high variability among strains, with the most efficient degrading over 90% of Impranil DLN. Protease activity was the most frequently detected enzymatic function, followed by urease and esterase activities. However, no clear correlation was observed between enzymatic profiles and degradation efficiency. Selected strains were tested on polyether PU foam, revealing biodegradative activity, an uncommon observation for bacteria on such recalcitrant material. These findings contribute to our understanding of bacterial diversity and enzymatic mechanisms involved in PU biodegradation, as well as their potential applications in plastic waste bioremediation.
Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support
(BioMed Central, 2025-12-12) Cáceres Palomo, Laura; Sánchez Mejías, Elisabeth; Trujillo Estrada, Laura; Pérez Moreno, Juan José; López Oliva, Elba; Lim, Tau En; DeFlitch, Leah; Vitorica Ferrández, Francisco Javier; García León, Juan Antonio; Gutiérrez, Antonia; Biología Celular; Bioquímica y Biología Molecular; Instituto de Salud Carlos III; European Union (UE)
Alzheimer´s disease (AD) is dominated by a complex cellular pathology which involves most brain cell types with glial cells increasingly recognized as playing fundamental roles in neurodegeneration. Astrocytes, which perform essential functions in preserving brain homeostasis, present a reactive phenotype in the AD brains with still unknown consequences. In this study, we generated and characterized human induced pluripotent stem cell (hiPSC)-derived astrocytes from AD patients harboring the APOE4/4 genotype, the greatest genetic risk factor for late-onset AD. Disease astrocytes showed a reactive phenotype. In addition, they showed altered mitochondrial network including perinuclear clustering of mitochondria, enhanced mitochondrial fusion and higher production of reactive oxygen species which, unexpectedly, were coincident with increased oxidative phosphorylation and glycolysis. As these mitochondrial features are related to the acquisition of cell senescence, we evaluated this at the transcriptome level and found that these AD-derived astrocytes significantly upregulated gene signatures of cellular senescence and displayed a senescence-associated secretory phenotype (SASP). To verify this finding, we observed senescence-related DNA damage response in a significant proportion of cells in the cerebral cortex of AD patients, with most of these cells being astrocytes. Finally, we confirmed that this astrocytic senescent and proinflammatory phenotype is associated with a reduced neuronal support, evidencing that APOE4/4 AD astrocytes present intrinsic features that may compromise brain homeostasis and promote neurodegeneration. Addressing the causes and consequences of this astrocytic dysfunctionality should help to elucidate novel therapeutic targets able to modify the neurodegeneration present in AD.
Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance
(Elsevier, 2015-06-26) Álvarez Sánchez, Nuria; Cruz Chamorro, Iván; López González, Antonio; Utrilla Alcolea, José Carmelo; Fernández-Santos, José María; Martínez López, Alicia; Lardone, Patricia Judith; Guerrero Montávez, Juan Miguel; Carrillo Vico, Antonio; Bioquímica Médica y Biología Molecular e Inmunología; Citología e Histología Normal y Patológica; Bioquímica y Biología Molecular; Instituto de Salud Carlos III; Gobierno de España; Junta de Andalucía; CTS439: Sistema Neuroendocrino Difuso; CTS160: NeuroInmunoEndocrinología Molecular
Experimental autoimmune encephalomyelitis (EAE), the experimental model for multiple sclerosis (MS), is triggered by myelin-specific Th1 and Th17 cells. The immunomodulatory activities of melatonin have been shown to be beneficial under several conditions in which the immune system is exacerbated. Here, we sought to elucidate the basis of the melatonin protective effect on EAE by characterizing the T effector/regulatory responses, particularly those of the memory cell subsets. Melatonin was tested for its effect on Th1, Th17 and T regulatory (Treg) cells in the lymph nodes and CNS of immunodominant peptide of myelin oligodendrocyte glycoprotein (pMOG)-immunized and EAE mice, respectively. The capacity of melatonin to ameliorate EAE as well as modifying both T cell response and effector/regulatory balance was surveyed. T cell memory subsets and CD44, a key activation marker involved in the EAE pathogenesis, were also examined. Melatonin protected from EAE by decreasing peripheral and central Th1/Th17 responses and enhancing both the Treg frequency and IL-10 synthesis in the CNS. Melatonin reduced the T effector memory population and its pro-inflammatory response and regulated CD44 expression, which was decreased in T effector cells and increased in Tregs. The alterations in the T cell subpopulations were associated with a reduced mononuclear infiltration (CD4 and CD11b cells) of the melatonin-treated mice CNS. For the first time, we report that melatonin protects against EAE by controlling peripheral and central T effector/regulatory responses, effects that might be partially mediated by CD44. This immunomodulatory effect on EAE suggests that melatonin may represent an effective treatment option for MS.
Galectin-3 shapes microglial phenotype through endogenous and exogenous mechanisms
(Frontiers Media S.A., 2025-12-18) Camprubí-Ferrer, Lluis; Yang, Yiyi; Fernández-Calle, Rosalía; Boza Serrano, Antonio; García Revilla, Juan; Frontiñán-Rubio, Javier; Deierborg, Tomas; Bioquímica y Biología Molecular
Galectin-3 (Gal3) is a multifunctional lectin expressed and released by microglia, where it influences diverse processes in both homeostasis and disease. To dissect its intracellular and extracellular roles, we generated Gal3-deficient BV2 microglial cells and systematically assessed how genetic deletion and exogenously added recombinant Gal3 shape microglial physiology. Gal3 deletion increased cell area, mitochondrial activity, and motility without affecting proliferation, linking endogenous Gal3 to microglial energetic control and dynamic cellular physiology. Endogenous Gal3 was required to maintain CD11b surface levels, and restrains TREM2 and Clec7a expression, whereas exogenous Gal3 promoted CD45 internalization and drove a paracrine TNFα release. Endogenous and exogenous Gal3 are synergistically needed for Syk phosphorylation and NOX2 expression. Internalization assays demonstrated that endogenous Gal3 constrained phagocytosis and endocytosis, while exogenous Gal3 enhanced endocytosis in a paracrine manner. In the Alzheimer’s disease 5xFAD mouse model, where Gal3 deletion was reported to lower amyloid plaque burden, the absence of Gal3 does not affect microgliosis but elevates Clec7a levels around plaques. Together, these findings reveal Gal3 as a critical regulator of microglial homeostasis, uptake pathways, receptor expression, and inflammatory signaling. We have defined a novel microglial regulation based on endogenous and exogenous pools of Gal3. By identifying a novel Gal3-Clec7a interaction, this work highlights Gal3 as a key modulator of microglial phenotype and a potential target for therapeutic modulation of neuroinflammation.
Galectin 3: A new player in the pathogenesis of Parkinson's disease
(Walters Kluwer, 2026) García Revilla, Juan; Venero Recio, José Luis; Rodríguez Gómez, José Antonio; Bioquímica y Biología Molecular; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España
Co-application of salicylic acid and potassium induce salinity tolerance by modulating ion homeostasis, chlorophyll pigments and photosynthetic apparatus in wheat
(Springer, 2025-11-12) Shaheen, Farzana; Ashraf, Muhammad Yasin; Hussain, Muhammad Iftikhar; Khan, Zafar Iqbal; Chaudhry, Usman Khalid; Abideen, Zainul; Parrado Rubio, Juan; Rahman, Muhammad Habib Ur; El-Keblawy, Ali; Bioquímica y Biología Molecular
Salinity is a major abiotic stress limiting global agricultural productivity, particularly affecting the physiological functions, nutrient uptake, and gas exchange processes of crops like wheat (Triticum aestivum L.). As salinization of arable land continues to expand, identifying effective and sustainable mitigation strategies is critical. This study evaluated the impact of foliar-applied salicylic acid (SA) (0, 0.01, 0.02, and 0.03%) and potassium (K) (0, 0.05, 0.1, and 0.15%) at two key growth stages (vegetative and grain filling) on two wheat varieties (WL-711 and Kohistan-97) grown under saline (120 mM NaCl; ≈12 dS/m) and non-saline conditions in a controlled pot experiment. Results showed that foliar application of SA (0.02%) and K (0.1%) significantly improved leaf nutrient concentrations (N, P, K, Ca, and Mg) and enhanced photosynthetic pigments (chlorophyll a, b, total chlorophyll, and carotenoids) under salt stress. These treatments also alleviated the adverse effects of salinity on gas exchange parameters, with WL-711 displaying higher tolerance than Kohistan-97. Overall, exogenous application of SA and K effectively improved physiological resilience and nutrient homeostasis in salt-stressed wheat. Notably, this study demonstrates, for the first time, the synergistic effect of optimal foliar doses of SA and K at two critical developmental stages, offering a practical and low-cost strategy to mitigate salinity stress in wheat. The findings provides a valuable basis for future field-scale interventions to enhance wheat productivity in salt-affected regions.
Tissue‐specific early and late activated lymphocytes immunophenotype in chronic rhinosinusitis with nasal polyps
(Wiley, 2024-01-24) López Enríquez, Soledad; Porras González, Cristina; Moreno‐Luna, Ramón; Palomares Jerez, María Francisca; Muñoz‐Bravo, José Luis; Alba Jiménez, Gonzalo; Santa-María Pérez, Consuelo; Maza Solano, Juan Manuel; Martín‐Jiménez, Daniel Iván; Pérez Pérez, Antonio; Moreno‐Luna, Rafael; Sánchez Margalet, Víctor; Sánchez Gómez, Serafín; Bioquímica Médica y Biología Molecular e Inmunología; Bioquímica y Biología Molecular; Cirugía; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España
Key points T-cell activation in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) is enriched by late cytotoxic T cells. The proportion of early and intermediate activated cytotoxic T cells decreases in nasal polyps of patients with CRSwNP. Our results identify late activated cytotoxic T cells as potential biomarkers or therapeutic targets for patients with CRSwNP.
Design of Fermentative Technology for the Valorization of Pig Bristle Keratins into Biostimulant for Agricultural Applications
(American Chemical Society (ACS), 2025-09-16) Orts, Ángel; López, Jesús; Orts Gómez, José María; Navarro Torre, Salvadora; Naranjo Fernández, Emilia; Caballero Jiménez, Pablo; Martín Presas, Luís; Castaño Navarro, Angélica; Parrado Rubio, Juan; Bioquímica y Biología Molecular; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
The elimination of keratin-derived waste, such as pig bristles, represents a significant challenge due to its high production levels and resistance to degradation. However, the keratinous composition also makes pig bristles a valuable waste material with significant potential for bioconversion into biostimulants rich in bioavailable nitrogen, peptides, and amino acids. To achieve degradation, microorganisms with keratinolytic activity isolated from the raw material were selected. Based on the best performance in plant PGP traits, solubility, and protease activity, Sporosarcina luteola was chosen to implement a fermentation technology that converts pig bristle waste. The fermented product comprises three classes of biostimulant components: the biomass of S. luteola, the enzymatic secretions of this microorganism, and the hydrolyzed organic matter from pig bristles, which is rich in protein hydrolysates and free amino acids. The biostimulant was evaluated in soil at the biochemical level (enzymatic activities) and in plants under oxidative stress, demonstrating a positive effect. These findings highlight the fermentation process using S. luteola as a promising strategy for the comprehensive valorization of pig bristle waste, resulting in products with significant agronomic and environmental benefits.
Effect of soil temperature and moisture on degradation of the oxyfluorfen herbicide
(Taylor & Francis, 2025-08-12) Paneque Macías, Patricia Isabel; Gómez Parrales, Isidoro Ángel; Parrado Rubio, Juan; Orts Gómez, José María; Tejada Moral, Manuel; Cristalografía, Mineralogía y Química Agrícola; Bioquímica y Biología Molecular; Ministerio de Ciencia e Innovación (MICIN). España
We have studied the combined effect of temperature and moisture on a soil contaminated with the oxyfluorfen herbicide at a dose of 4 l ha−1 in terms of the biochemical activity (dehydrogenase activity and ergosterol content) of said soil, as well as on the concentration of said herbicide over a 90-day period in a laboratory setting. Two degrees of moisture were used: (1) irrigated soils maintained at 60% of their water retention capacity and (2) non-irrigated soils (non-watered soils, without irrigation). These treatments were subjected to three temperatures (4 °C, 25 °C, and 40 °C, respectively). In all cases, the oxyfluorfen caused a toxic effect on both the dehydrogenase activity and ergosterol content of the soil. However, this toxic effect was greater in non-watered soils, possibly due to the combined effect of the herbicide toxicity and the soil drought conditions. With regard to temperature, the results indicate that dehydrogenase activity and ergosterol content in soil were more negatively affected when samples were incubated at higher temperatures (40 °C). Statistical analysis suggests that temperature may have a greater specific weight or influence than soil moisture, since a variation in temperature causes a variation in soil moisture.
Effective Validation of Primary Care Patient Triage Classification Via Tele-Ophthalmology With Optometrist Support
(SAGE Publications, 2025-08-27) Carrasco Solís, Rafael; Rodríguez Griñolo, María Rosario; Ponte Zúñiga, Beatriz; Mataix Albert, Beatriz; González Troncoso, María José; Martínez de Pablos, Rocío; Rodríguez de la Rúa Franch, Enrique; Bioquímica y Biología Molecular; Cirugía; Instituto de Salud Carlos III
The triage classification and diagnosis of eye diseases in primary care patients through teleophthalmology were performed by ophthalmologists, optometrists, and family physicians. The agreement in triage classification and diagnosis between observers, as well as the quality of referrals from primary care to ophthalmology, were evaluated. Study to compare methods using a non-inferiority method approach. The sample comprised 220 patients with suspected ocular problems evaluated by family physicians. These patients were examined by an optometrist (observer 1) using a Visionix VX650 multi-diagnostic platform. The optometrist provided a suspected diagnosis and a referral. The tests were forwarded electronically to an ophthalmologist (observer 2), who provided a diagnosis and referral. Subsequently, they were reviewed in person by an ophthalmologist (observer 3) who provided a diagnosis and referral. The observers worked independently and at different times, without knowledge of each other’s evaluations, ensuring the objectivity of the analysis. We analyzed interobserver agreement in triage referrals and diagnosis using the Kappa index. The triage classification of patients by teleophthalmology coincides with that of in-person ophthalmology in 91.2% of the cases (Kappa = 0.819). The optician’s triage classification coincided with in-person ophthalmology in 91.3% (Kappa = 0.858) and with teleophthalmology in 92.3% (Kappa = 0.851). The diagnostic categories, teleophthalmology and in-person ophthalmology coincided in 84.61% of the cases (Kappa = 0.80). The optician coincided with in-person ophthalmology in 90.65% (Kappa = 0.88) and with teleophthalmology in 90.9% of the diagnoses (Kappa = 0.87). There was a very high level interobserver agreement for both triage classification and diagnostic categories. This validates our teleophthalmology approach, conducted in a primary care setting by optometrists, family physicians, and ophthalmologists, for an effective triage classification of patients referred to ophthalmology services. This telemedicine also accurately categorizes patients based on their conditions, optimizing resources, reducing waiting times and waiting lists.
Inactivation of the PHD3-FOXO3 axis blunts the type I interferon response in microglia and ameliorates Alzheimer’s disease progression
(American Association for the Advancement of Science (AAAS), 2025-05-28) Sánchez-García, Manuel A.; Cabello Rivera, Daniel; Romero Molina, Carmen; Navarro Garrido, Victoria; López Barneo, José; Vizuete Chacón, María Luisa; Muñoz Cabello, Ana María; Rosales Nieves, Alicia E.; Pascual, Alberto; Bioquímica y Biología Molecular; Fisiología Médica y Biofísica; Agencia Estatal de Investigación. España; Ministerio de Ciencia e Innovación (MICIN). España; European Union (UE); Cancer Research. United Kingdom; Junta de Andalucía; Medical Research Council. United Kingdom; Universidad de Sevilla; Wellcome Trust. United Kingdom
Microglia respond to Alzheimer’s disease (AD) with varied transcriptional responses. We show that oligomeric Aß (oAß) induces the expression of Hif1a and Egln3 in microglia in vitro, together with the transcription of the type I interferon signature (IFNS) genes in a PHD3-dependent manner. We identify FOXO3 as a repressor of IFNS, whose abundance decreases upon PHD3 induction in response to oAß. In vivo, loss of PHD3 correlates with abrogation of the IFNS and activation of the disease-associated microglia signature, an increase in microglia proximity to Aß plaques and phagocytosis of both Aß and small plaques. PHD3 deficiency mitigated the Aß plaque–associated neuropathology and rescued behavioral deficits of an AD mouse model. Last, we demonstrate that microglial PHD3 overexpression in the absence of Aß pathology is sufficient to induce the IFNS and behavioral alterations. Together, our data strongly indicate that the inactivation of the PHD3-FOXO3 axis controls the microglial IFNS in a cell autonomous manner, improving AD outcome.
Distinct and redundant roles of the Arabidopsis OCTOPUS gene family in plant growth beyond phloem development
(Oxford University Press, 2025-01-11) Crivelli, Simona; Bartusch, Kai; Ruiz Sola, M. Águila; Coiro, Mario; Schmidt Kjolner Hansen, Signe; Truernit, Elisabeth; Bioquímica y Biología Molecular
The Arabidopsis root apical meristem is an excellent model for studying plant organ growth. This involves a coordinated process of cell division, elongation, and differentiation, with each tissue type developing according to its own schedule. Among these tissues, the protophloem is particularly important, differentiating early to supply nutrients and signalling molecules to the growing root tip. The OCTOPUS (OPS) protein and its homologue OPS-LIKE 2 (OPL2) are essential for proper root protophloem differentiation and, probably through this role, indirectly promote root growth. Here, we explored the roles of the other three OPS homologues in Arabidopsis, OPL1, OPL3, and OPL4. OPS/OPL genes exhibited overlapping expression patterns and functions, with a high degree of redundancy among them. Although higher order mutants did not display more severe phloem defects, they exhibited significantly reduced root growth compared with the ops opl2 mutant. These results indicate a direct contribution of the investigated OPL genes to meristematic activity. While our focus was on root growth, the OPS/OPL gene family also plays a positive role in regulating shoot growth, emphasizing its broader impact on plant development. Furthermore, our analyses reiterate the central role of OPS and the phloem domain in controlling overall plant growth.
The role of microglia in the prion-like transmission of protein aggregates in neurodegeneration
(Oxford University Press, 2025-02-25) Öztürk, Muhammet M.; Emgård, Jakob; García Revilla, Juan; Fernández-Calle, Rosalía; Yang, Yiyi; Deierborg, Tomas; Roos, Tomas T.; Bioquímica y Biología Molecular
Numerous neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis share a neuropathological hallmark: aberrant protein aggregation in the CNS. Microglia, the brain’s innate immune cells, also play a pivotal role in the pathogenesis of these disorders. Multiple studies indicate that these pathological aggregates can propagate throughout the brain in a prion-like manner. A protein/peptide that adopts a prion-like conformation can induce homologous proteins to misfold into a prion-like conformation through templated seeding, enabling cell-to-cell spread and accelerating protein aggregation throughout the brain. Two important questions in the prion-like paradigm are where the prion-like misfolding occurs and how the prion-like aggregates are spread throughout the CNS. Here, we review the role of microglia and associated inflammation in the prion-like spread of pathologically aggregated proteins/peptides in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that microglia can internalize prion-like proteins and transport them to neighbouring neurons and other glial cells. Microglia may also influence the potential seeding of proteins in neurons and induce inflammatory pathways in their microenvironment. This review aims to broaden the understanding of the role of microglia in the prion-like spread of protein aggregation.
Intergenerational Influence of Paternal Obesity on Metabolic and Reproductive Health Parameters of the Offspring: Male-Preferential Impact and Involvement of Kiss1-Mediated Pathways
(Oxford University Press, 2018-02) Sanchez-Garrido, M. A.; Ruiz-Pino, F.; Velasco, I.; Barroso, A.; Fernandois, D.; Manfredi Lozano, María; Tena-Sempere, M.; Bioquímica y Biología Molecular; Ministerio de Economía y Competitividad (MINECO). España; Ministerio de Sanidad. España; Junta de Andalucía; European Commission (EC)
Obesity and its comorbidities are reaching epidemic proportions worldwide. Maternal obesity is known to predispose the offspring to metabolic disorders, independently of genetic inheritance. This intergenerational transmission has also been suggested for paternal obesity, with a potential negative impact on the metabolic and, eventually, reproductive health of the offspring, likely via epigenetic changes in spermatozoa. However, the neuroendocrine component of such phenomenon and whether paternal obesity sensitizes the offspring to the disturbances induced by high-fat diet (HFD) remain poorly defined. We report in this work the metabolic and reproductive impact of HFD in the offspring from obese fathers, with attention to potential sex differences and alterations of hypothalamic Kiss1 system. Lean and obese male rats were mated with lean virgin female rats; male and female offspring were fed HFD from weaning onward and analyzed at adulthood. The increases in body weight and leptin levels, but not glucose intolerance, induced by HFD were significantly augmented in the male, but not female, offspring from obese fathers. Paternal obesity caused a decrease in luteinizing hormone (LH) levels and exacerbated the drop in circulating testosterone and gene expression of its key biosynthetic enzymes caused by HFD in the male offspring. LH responses to central kisspeptin-10 administration were also suppressed in HFD males from obese fathers. In contrast, paternal obesity did not significantly alter gonadotropin levels in the female offspring fed HFD, although these females displayed reduced LH responses to kisspeptin10. Our findings suggest that HFD-induced metabolic and reproductive disturbances are exacerbated by paternal obesity preferentially in males, whereas kisspeptin effects are affected in both sexes.
ETS transcription factor pointed controls germline survival in Drosophila
(PLOS, 2025-08-25) Rosales Nieves, Alicia E.; Marín-Menguiano, M.; López-Onieva, L.; Garrido-Maraver, J.; González-Reyes, A.; Bioquímica y Biología Molecular; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Junta de Andalucía
Proper gonad development is a pre-requisite for gametogenesis and reproduction. During female gonad formation in Drosophila, the EGF receptor (EGFR) signalling pathway ensures the correct number of primordial germ cells (PGCs) populate the larval gonad. We study the gene pointed (pnt), which acts downstream of the EGFR receptor and belongs to the ETS transcription factor family, with a previously unknown function in gonadogenesis. We report that pnt is expressed in female larval gonads and later in the adult ovarian germline niche and that it is required to sustain proper gametogenesis. Loss of pnt function in female larval gonads, similar to the EGFR, induced PGC overproliferation. Conversely, we isolated a novel mutant allele gene, termed pntaga, which resulted in agametic gonads and ovaries. While pntaga embryos developed gonads containing a normal complement of PGCs, these are subsequently lost by apoptosis during late larval and pupal stages. Molecular characterization of pntaga revealed reduced expression levels of the different pnt isoforms, unveiling a complex autoregulatory network involving the three Pnt proteins. We propose that germline survival in Drosophila gonads requires a precise tuning of EGFR signalling to ensure the appropriate transcriptional activation of its target pnt.
Amyloid structural changes studied by infrared microspectroscopy in bigenic cellular models of alzheimer’s disease
(MDPI, 2021-03-26) Paulus, Agnes; Engdahl, Anders; Yang, Yiyi; Boza Serrano, Antonio; Bachiller, Sara; Torres-Garcia, Laura; Klementieva, Oxana; Bioquímica y Biología Molecular; Bioquímica Médica y Biología Molecular e Inmunología; BIO113: Mecanismos de Muerte Celular en Enfermedades Neurodegenerativas
Alzheimer’s disease affects millions of lives worldwide. This terminal disease is characterized by the formation of amyloid aggregates, so-called amyloid oligomers. These oligomers are composed of β-sheet structures, which are believed to be neurotoxic. However, the actual secondary structure that contributes most to neurotoxicity remains unknown. This lack of knowledge is due to the challenging nature of characterizing the secondary structure of amyloids in cells. To overcome this and investigate the molecular changes in proteins directly in cells, we used synchrotron-based infrared microspectroscopy, a label-free and non-destructive technique available for in situ molecular imaging, to detect structural changes in proteins and lipids. Specifically, we evaluated the formation of β-sheet structures in different monogenic and bigenic cellular models of Alzheimer’s disease that we generated for this study. We report on the possibility to discern different amyloid signatures directly in cells using infrared microspectroscopy and demonstrate that bigenic (amyloid-β, α-synuclein) and (amyloid-β, Tau) neuron-like cells display changes in β-sheet load. Altogether, our findings support the notion that different molecular mechanisms of amyloid aggregation, as opposed to a common mechanism, are triggered by the specific cellular environment and, therefore, that various mechanisms lead to the development of Alzheimer’s disease.
An Insertion Within SIRPbeta1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response
(IOS Press BV, 2024-03) García-Alberca, José María; de Rojas, Itziar; Sánchez-Mejías, Elisabeth; Garrido-Martín, Diego; González-Palma, Laura; Jiménez, Sebastián; Muñoz Castro, Clara; Navarro Garrido, Victoria; Mir Rivera, Pablo; Vitorica Ferrández, Francisco Javier; GERALD consortium; Bioquímica y Biología Molecular; Medicina; Ministerio de Ciencia e Innovación (MICIN). España; Instituto de Salud Carlos III; Junta de Andalucía
Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers amyloid-β(Aβ) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p=0.018) and a higher risk to develop AD (OR=1.678, p=0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p<0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p=0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway.

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