8 results on '"Enrique Santamaria"'
Search Results
2. PROTEOMIC PROFILING OF TWO MULTIPLE SCLEROSIS MOUSE MODELS
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Sonsoles Barriola, Lina Delgado García, Paz Cartas Cejudo, Ignacio Iñigo-Marco, Joaquin Fernandez-Irigoyen, Enrique Santamaria-Martinez, and Laura López-Mascaraque
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2023
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3. Stabilization of 14-3-3 protein-protein interactions with Fusicoccin-A decreases alpha-synuclein dependent cell-autonomous death in neuronal and mouse models
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Rodrigo Vinueza-Gavilanes, Jorge Juan Bravo-González, Leyre Basurco, Chiara Boncristiani, Joaquín Fernández-Irigoyen, Enrique Santamaría, Irene Marcilla, Alberto Pérez-Mediavilla, María Rosario Luquin, Africa Vales, Gloria González-Aseguinolaza, María Soledad Aymerich, Tomás Aragón, and Montserrat Arrasate
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Alpha-synuclein ,Parkinson's disease ,Synucleinopathies ,Neuronal death ,Proximity biotinylation ,BioID2 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Synucleinopathies are a group of neurodegenerative diseases without effective treatment characterized by the abnormal aggregation of alpha-synuclein (aSyn) protein. Changes in levels or in the amino acid sequence of aSyn (by duplication/triplication of the aSyn gene or point mutations in the encoding region) cause familial cases of synucleinopathies. However, the specific molecular mechanisms of aSyn-dependent toxicity remain unclear. Increased aSyn protein levels or pathological mutations may favor abnormal protein-protein interactions (PPIs) that could either promote neuronal death or belong to a coping response program against neurotoxicity. Therefore, the identification and modulation of aSyn-dependent PPIs can provide new therapeutic targets for these diseases. To identify aSyn-dependent PPIs we performed a proximity biotinylation assay based on the promiscuous biotinylase BioID2. When expressed as a fusion protein, BioID2 biotinylates by proximity stable and transient interacting partners, allowing their identification by streptavidin affinity purification and mass spectrometry. The aSyn interactome was analyzed using BioID2-tagged wild-type (WT) and pathological mutant E46K aSyn versions in HEK293 cells. We found the 14-3-3 epsilon isoform as a common protein interactor for WT and E46K aSyn. 14‐3-3 epsilon correlates with aSyn protein levels in brain regions of a transgenic mouse model overexpressing WT human aSyn. Using a neuronal model in which aSyn cell-autonomous toxicity is quantitatively scored by longitudinal survival analysis, we found that stabilization of 14‐3-3 protein-proteins interactions with Fusicoccin-A (FC-A) decreases aSyn-dependent toxicity. Furthermore, FC-A treatment protects dopaminergic neuronal somas in the substantia nigra of a Parkinson's disease mouse model. Based on these results, we propose that the stabilization of 14‐3-3 epsilon interaction with aSyn might reduce aSyn toxicity, and highlight FC-A as a potential therapeutic compound for synucleinopathies.
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- 2023
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4. Biomarkers of delirium risk in older adults: a systematic review and meta-analysis
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Lucía Lozano-Vicario, Antonio García-Hermoso, Bernardo Abel Cedeno-Veloz, Joaquín Fernández-Irigoyen, Enrique Santamaría, Román Romero-Ortuno, Fabricio Zambom-Ferraresi, Mikel L. Sáez de Asteasu, Ángel Javier Muñoz-Vázquez, Mikel Izquierdo, and Nicolás Martínez-Velilla
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delirium ,cognitive impairment ,biomarkers ,neuroinflammation ,older people ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Delirium is a neuropsychiatric syndrome associated with increased morbidity and mortality in older patients. The aim of this study was to review predictive biomarkers of delirium in older patients to gain insights into the pathophysiology of this syndrome and provide guidance for future studies. Two authors independently and systematically searched MEDLINE, Embase, Cochrane Library, Web of Science and Scopus databases up to August 2021. A total of 32 studies were included. Only 6 studies were eligible for the meta-analysis, pooled results showed a significant increase in some serum biomarkers (C-reactive protein [CRP], tumour necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]) among patients with delirium (odds ratio = 1.88, 95% CI 1.01 to 1.637; I2 = 76.75%). Although current evidence does not favour the use of any particular biomarker, serum CRP, TNF-α, and IL-6 were the most consistent biomarkers of delirium in older patients.
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- 2023
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5. Effectiveness of a multicomponent exercise training program for the management of delirium in hospitalized older adults using near-infrared spectroscopy as a biomarker of brain perfusion: Study protocol for a randomized controlled trial
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Lucía Lozano-Vicario, Fabiola Zambom-Ferraresi, Fabricio Zambom-Ferraresi, Antón de la Casa-Marín, Iranzu Ollo-Martínez, Mikel L. Sáez de Asteasu, Bernardo Abel Cedeño-Veloz, Joaquín Fernández-Irigoyen, Enrique Santamaría, Román Romero-Ortuno, Mikel Izquierdo, and Nicolás Martínez-Velilla
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delirium ,near-infrared spectroscopy ,multicomponent intervention ,older adults ,physical exercise ,geriatric acute care unit ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Delirium is an important cause of morbidity and mortality in older adults admitted to hospital. Multicomponent interventions targeting delirium risk factors, including physical exercise and mobilization, have been shown to reduce delirium incidence by 30–40% in acute care settings. However, little is known about its role in the evolution of delirium, once established. This study is a randomized clinical trial conducted in the Acute Geriatric Unit of Hospital Universitario de Navarra (Pamplona, Spain). Hospitalized patients with delirium who meet the inclusion criteria will be randomly assigned to the intervention or the control group. The intervention will consist of a multicomponent exercise training program, which will be composed of supervised progressive resistance and strength exercise over 3 consecutive days. Functional Near-Infrared Spectroscopy (NIRS) will be used for assessing cerebral and muscle tissue blood flow. The objective is to assess the effectiveness of this intervention in modifying the following primary outcomes: duration and severity of delirium and functional status. This study will contribute to determine the effectiveness of physical exercise in the management of delirium. It will be the first study to evaluate the impact of a multicomponent intervention based on physical exercise in the evolution of delirium.Clinical trial registrationClinicalTrials.gov. identifier: NCT05442892 (date of registration June 26, 2022).
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- 2022
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6. Olfactory Characterization and Training in Older Adults: Protocol Study
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Fabíola Zambom-Ferraresi, Fabricio Zambom-Ferraresi, Joaquín Fernández-Irigoyen, Mercedes Lachén-Montes, Paz Cartas-Cejudo, Juan José Lasarte, Noelia Casares, Secundino Fernández, Bernardo Abel Cedeño-Veloz, Enrique Maraví-Aznar, Maria Itziar Uzcanga-Lacabe, Arkaitz Galbete, Enrique Santamaría, and Nicolás Martínez-Velilla
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smell sense ,olfactory dysfunction ,immune fitness ,odor training ,geriatric ,neurodegenerative disease ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The aim of this article is to present the research protocol for a prospective cohort study that will assess the olfactory function and the effect of an intervention based on olfactory training in healthy very old adults (≥75 years old). A convenience sample of 180 older people (50% female) will be recruited in three different environments: hospitalized control group (CH) with stable acute illness (n = 60); ambulatory control group (CA) of community-based living (n = 60); and an experimental odor training group (EOT) from nursing homes (n = 60). The odor training (OT) intervention will last 12 weeks. All the volunteers will be assessed at baseline; CA and EOT groups will also be assessed after 12 weeks. The primary end point will be change in olfactory capacity from baseline to 12 weeks period of intervention or control. The intervention effects will be assessed with the overall score achieved in Sniffin Sticks Test (SST) – Threshold, Discrimination, and Identification (TDI) extended version. Secondary end points will be changes in cognitive tasks, quality of life, mood, immune status, and functional capacity. All these measurements will be complemented with an immune fitness characterization and a deep proteome profiling of the olfactory epithelium (OE) cultured ex vivo. The current study will provide additional evidence to support the implementation of olfactory precision medicine and the development of immunomodulatory nasal therapies based on non-invasive procedures. The proposed intervention will also intend to increase the knowledge about the olfactory function in very elderly people, improve function and quality of life, and promote the recovery of the health.
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- 2021
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7. N-terminal acetylation mutants affect alpha-synuclein stability, protein levels and neuronal toxicity
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Rodrigo Vinueza-Gavilanes, Ignacio Íñigo-Marco, Laura Larrea, Marta Lasa, Beatriz Carte, Enrique Santamaría, Joaquín Fernández-Irigoyen, Ricardo Bugallo, Tomás Aragón, Rafael Aldabe, and Montserrat Arrasate
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Alpha-synuclein ,N-terminal acetylation ,Longitudinal survival analysis ,Cox proportional hazard analysis ,Optical pulse-labeling ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Alpha-synuclein (aSyn) protein levels are sufficient to drive Parkinson's disease (PD) and other synucleinopathies. Despite the biomedical/therapeutic potential of aSyn protein regulation, little is known about mechanisms that limit/control aSyn levels. Here, we investigate the role of a post-translational modification, N-terminal acetylation, in aSyn neurotoxicity. N-terminal acetylation occurs in all aSyn molecules and has been proposed to determine its lipid binding and aggregation capacities; however, its effect in aSyn stability/neurotoxicity has not been evaluated. We generated N-terminal mutants that alter or block physiological aSyn N-terminal acetylation in wild-type or pathological mutant E46K aSyn versions and confirmed N-terminal acetylation status by mass spectrometry. By optical pulse-labeling in living primary neurons we documented a reduced half-life and accumulation of aSyn N-terminal mutants. To analyze the effect of N-terminal acetylation mutants in neuronal toxicity we took advantage of a neuronal model where aSyn toxicity was scored by longitudinal survival analysis. Salient features of aSyn neurotoxicity were previously investigated with this approach. aSyn-dependent neuronal death was recapitulated either by higher aSyn protein levels in the case of WT aSyn, or by the combined effect of protein levels and enhanced neurotoxicity conveyed by the E46K mutation. aSyn N-terminal mutations decreased E46K aSyn-dependent neuronal death both by reducing protein levels and, importantly, by reducing the intrinsic E46K aSyn toxicity, being the D2P mutant the least toxic. Together, our results illustrate that the N-terminus determines, most likely through its acetylation, aSyn protein levels and toxicity, identifying this modification as a potential therapeutic target.
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- 2020
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8. Early-Onset Molecular Derangements in the Olfactory Bulb of Tg2576 Mice: Novel Insights Into the Stress-Responsive Olfactory Kinase Dynamics in Alzheimer’s Disease
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Mercedes Lachen-Montes, Andrea González-Morales, Maialen Palomino, Karina Ausin, Marta Gómez-Ochoa, María Victoria Zelaya, Isidro Ferrer, Alberto Pérez-Mediavilla, Joaquín Fernández-Irigoyen, and Enrique Santamaría
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Alzheimer’s disease ,olfactory bulb ,network biology ,proteomics ,transcriptomics ,Tg2576 mice ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The olfactory bulb (OB) is the first processing station in the olfactory pathway. Despite smell impairment, which is considered an early event in Alzheimer’s disease (AD), little is known about the initial molecular disturbances that accompany the AD development at olfactory level. We have interrogated the time-dependent OB molecular landscape in Tg2576 AD mice prior to the appearance of neuropathological amyloid plaques (2-, and 6-month-old), using combinatorial omics analysis. The metabolic modulation induced by overproduction of human mutated amyloid precursor protein (APP) clearly differs between both time points. Besides the progressive perturbation of the APP interactome, functional network analysis unveiled an inverse regulation of downstream extracellular signal-regulated kinase (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) routes in 2-month-old Tg2576 mice with respect to wild-type (WT) mice. In contrast, Akt and MAPK kinase 4 (SEK1)/ stress-activated protein kinase (SAPK) axis were parallel activated in the OB of 6-months-old-Tg2576 mice. Furthermore, a survival kinome profiling performed during the aging process (2-, 6-, and 18-month-old) revealed that olfactory APP overexpression leads to changes in the activation dynamics of protein kinase A (PKA), and SEK1/MKK4-SAPK/JNK between 6 and 18 months of age, when memory deficits appear and AD pathology is well established in transgenic mice. Interestingly, both olfactory pathways were differentially activated in a stage-dependent manner in human sporadic AD subjects with different neuropathological grading. Taken together, our data reflect the early impact of mutated APP on the OB molecular homeostasis, highlighting the progressive modulation of specific signaling pathways during the olfactory amyloidogenic pathology.
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- 2019
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