22 results on '"Paz Cartas-Cejudo"'
Search Results
2. Involvement of Glucosamine 6 Phosphate Isomerase 2 (GNPDA2) Overproduction in β-Amyloid- and Tau P301L-Driven Pathomechanisms
- Author
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Mercedes Lachén-Montes, Paz Cartas-Cejudo, Adriana Cortés, Elena Anaya-Cubero, Erika Peral, Karina Ausín, Ramón Díaz-Peña, Joaquín Fernández-Irigoyen, and Enrique Santamaría
- Subjects
GNPDA2 ,neurodegeneration ,olfaction ,zebrafish ,Microbiology ,QR1-502 - Abstract
Alzheimer’s disease (AD) is a neurodegenerative olfactory disorder affecting millions of people worldwide. Alterations in the hexosamine- or glucose-related pathways have been described through AD progression. Specifically, an alteration in glucosamine 6 phosphate isomerase 2 (GNPDA2) protein levels has been observed in olfactory areas of AD subjects. However, the biological role of GNPDA2 in neurodegeneration remains unknown. Using mass spectrometry, multiple GNPDA2 interactors were identified in human nasal epithelial cells (NECs) mainly involved in intraciliary transport. Moreover, GNPDA2 overexpression induced an increment in NEC proliferation rates, accompanied by transcriptomic alterations in Type II interferon signaling or cellular stress responses. In contrast, the presence of beta-amyloid or mutated Tau-P301L in GNPDA2-overexpressing NECs induced a slowdown in the proliferative capacity in parallel with a disruption in protein processing. The proteomic characterization of Tau-P301L transgenic zebrafish embryos demonstrated that GNPDA2 overexpression interfered with collagen biosynthesis and RNA/protein processing, without inducing additional changes in axonal outgrowth defects or neuronal cell death. In humans, a significant increase in serum GNPDA2 levels was observed across multiple neurological proteinopathies (AD, Lewy body dementia, progressive supranuclear palsy, mixed dementia and amyotrophic lateral sclerosis) (n = 215). These data shed new light on GNPDA2-dependent mechanisms associated with the neurodegenerative process beyond the hexosamine route.
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- 2024
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3. Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells
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Noelia Casares, María Alfaro, Mar Cuadrado-Tejedor, Aritz Lasarte-Cia, Flor Navarro, Isabel Vivas, María Espelosin, Paz Cartas-Cejudo, Joaquín Fernández-Irigoyen, Enrique Santamaría, Ana García-Osta, and Juan José Lasarte
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immunomodulation ,menthol ,methimazole ,olfactory system ,Treg cells ,central nervous system ,Immunologic diseases. Allergy ,RC581-607 - Abstract
A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use of an immunostimulatory odorant like menthol, analyzing its impact on the immune system and the cognitive capacity in healthy and Alzheimer’s Disease Mouse Models. We first found that repeated short exposures to menthol odor enhanced the immune response against ovalbumin immunization. Menthol inhalation also improved the cognitive capacity of immunocompetent mice but not in immunodeficient NSG mice, which exhibited very poor fear-conditioning. This improvement was associated with a downregulation of IL-1β and IL-6 mRNA in the brain´s prefrontal cortex, and it was impaired by anosmia induction with methimazole. Exposure to menthol for 6 months (1 week per month) prevented the cognitive impairment observed in the APP/PS1 mouse model of Alzheimer. Besides, this improvement was also observed by the depletion or inhibition of T regulatory cells. Treg depletion also improved the cognitive capacity of the APPNL-G-F/NL-G-F Alzheimer´s mouse model. In all cases, the improvement in learning capacity was associated with a downregulation of IL-1β mRNA. Blockade of the IL-1 receptor with anakinra resulted in a significant increase in cognitive capacity in healthy mice as well as in the APP/PS1 model of Alzheimer´s disease. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals, highlighting the potential of odors and immune modulators as therapeutic agents for CNS-related diseases.
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- 2023
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4. Deregulated Transcription and Proteostasis in Adult mapt Knockout Mouse
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Pol Andrés-Benito, África Flores, Sara Busquet-Areny, Margarita Carmona, Karina Ausín, Paz Cartas-Cejudo, Mercedes Lachén-Montes, José Antonio Del Rio, Joaquín Fernández-Irigoyen, Enrique Santamaría, and Isidro Ferrer
- Subjects
tau-KO ,transcriptomics ,phosphoproteomics ,cytoskeleton ,synapse ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Transcriptomics and phosphoproteomics were carried out in the cerebral cortex of B6.Cg-Mapttm1(EGFP)Klt (tau knockout: tau-KO) and wild-type (WT) 12 month-old mice to learn about the effects of tau ablation. Compared with WT mice, tau-KO mice displayed reduced anxiety-like behavior and lower fear expression induced by aversive conditioning, whereas recognition memory remained unaltered. Cortical transcriptomic analysis revealed 69 downregulated and 105 upregulated genes in tau-KO mice, corresponding to synaptic structures, neuron cytoskeleton and transport, and extracellular matrix components. RT-qPCR validated increased mRNA levels of col6a4, gabrq, gad1, grm5, grip2, map2, rab8a, tubb3, wnt16, and an absence of map1a in tau-KO mice compared with WT mice. A few proteins were assessed with Western blotting to compare mRNA expression with corresponding protein levels. Map1a mRNA and protein levels decreased. However, β-tubulin III and GAD1 protein levels were reduced in tau-KO mice. Cortical phosphoproteomics revealed 121 hypophosphorylated and 98 hyperphosphorylated proteins in tau-KO mice. Deregulated phosphoproteins were categorized into cytoskeletal (n = 45) and membrane proteins, including proteins of the synapses and vesicles, myelin proteins, and proteins linked to membrane transport and ion channels (n = 84), proteins related to DNA and RNA metabolism (n = 36), proteins connected to the ubiquitin-proteasome system (UPS) (n = 7), proteins with kinase or phosphatase activity (n = 21), and 22 other proteins related to variegated pathways such as metabolic pathways, growth factors, or mitochondrial function or structure. The present observations reveal a complex altered brain transcriptome and phosphoproteome in tau-KO mice with only mild behavioral alterations.
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- 2023
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5. 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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6. Docosahexaenoic Acid Ameliorates Contextual Fear Memory Deficits in the Tg2576 Alzheimer’s Disease Mouse Model: Cellular and Molecular Correlates
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Sara Badesso, Paz Cartas-Cejudo, Maria Espelosin, Enrique Santamaria, Mar Cuadrado-Tejedor, and Ana Garcia-Osta
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Alzheimer’s disease ,DHA ,synapse ,Pharmacy and materia medica ,RS1-441 - Abstract
Docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the brain, is essential for successful aging. In fact, epidemiological studies have demonstrated that increased intake of DHA might lower the risk for developing Alzheimer’s disease (AD). These observations are supported by studies in animal models showing that DHA reduces synaptic pathology and memory deficits. Different mechanisms to explain these beneficial effects have been proposed; however, the molecular pathways involved are still unknown. In this study, to unravel the main underlying molecular mechanisms activated upon DHA treatment, the effect of a high dose of DHA on cognitive function and AD pathology was analyzed in aged Tg2576 mice and their wild-type littermates. Transcriptomic analysis of mice hippocampi using RNA sequencing was subsequently performed. Our results revealed that, through an amyloid-independent mechanism, DHA enhanced memory function and increased synapse formation only in the Tg2576 mice. Likewise, the IPA analysis demonstrated that essential neuronal functions related to synaptogenesis, neuritogenesis, the branching of neurites, the density of dendritic spines and the outgrowth of axons were upregulated upon-DHA treatment in Tg2576 mice. Our results suggest that memory function in APP mice is influenced by DHA intake; therefore, a high dose of daily DHA should be tested as a dietary supplement for AD dementia prevention.
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- 2022
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7. Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model
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Isidro Ferrer, Pol Andrés-Benito, Karina Ausín, Paz Cartas-Cejudo, Mercedes Lachén-Montes, José Antonio del Rio, Joaquín Fernández-Irigoyen, and Enrique Santamaría
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hTau ,phosphorylation ,tau ,membrane ,cytoskeleton ,synapsis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Altered protein phosphorylation is a major pathologic modification in tauopathies and Alzheimer’s disease (AD) linked to abnormal tau fibrillar deposits in neurofibrillary tangles (NFTs) and pre-tangles and β-amyloid deposits in AD. hTau transgenic mice, which express 3R and less 4R human tau with no mutations in a murine knock-out background, show increased tau deposition in neurons but not NFTs and pre-tangles at the age of nine months. Label-free (phospho)proteomics and SWATH-MS identified 2065 proteins in hTau and wild-type (WT) mice. Only six proteins showed increased levels in hTau; no proteins were down-regulated. Increased tau phosphorylation in hTau was detected at Ser199, Ser202, Ser214, Ser396, Ser400, Thr403, Ser404, Ser413, Ser416, Ser422, Ser491, and Ser494, in addition to Thr181, Thr231, Ser396/Ser404, but not at Ser202/Thr205. In addition, 4578 phosphopeptides (corresponding to 1622 phosphoproteins) were identified in hTau and WT mice; 64 proteins were differentially phosphorylated in hTau. Sixty proteins were grouped into components of membranes, membrane signaling, synapses, vesicles, cytoskeleton, DNA/RNA/protein metabolism, ubiquitin/proteasome system, cholesterol and lipid metabolism, and cell signaling. These results showed that over-expression of human tau without pre-tangle and NFT formation preferentially triggers an imbalance in the phosphorylation profile of specific proteins involved in the cytoskeletal–membrane-signaling axis.
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- 2022
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8. Tackling the Biological Meaning of the Human Olfactory Bulb Dyshomeostatic Proteome across Neurological Disorders: An Integrative Bioinformatic Approach
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Paz Cartas-Cejudo, Mercedes Lachén-Montes, Joaquín Fernández-Irigoyen, and Enrique Santamaría
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olfactory bulb ,neurodegeneration ,proteomics ,pathways ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Olfactory dysfunction is considered an early prodromal marker of many neurodegenerative diseases. Neuropathological changes and aberrant protein aggregates occur in the olfactory bulb (OB), triggering a tangled cascade of molecular events that is not completely understood across neurological disorders. This study aims to analyze commonalities and differences in the olfactory protein homeostasis across neurological backgrounds with different spectrums of smell dysfunction. For that, an integrative analysis was performed using OB proteomics datasets derived from subjects with Alzheimer’s disease (AD), Parkinson’s disease (PD), mixed dementia (mixD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration (FTLD-TDP43), progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) with respect to OB proteome data from neurologically intact controls. A total of 80% of the differential expressed protein products were potentially disease-specific whereas the remaining 20% were commonly altered across two, three or four neurological phenotypes. A multi-level bioinformatic characterization revealed a subset of potential disease-specific transcription factors responsible for the downstream effects detected at the proteome level as well as specific densely connected protein complexes targeted by several neurological phenotypes. Interestingly, common or unique pathways and biofunctions were also identified, providing novel mechanistic clues about each neurological disease at olfactory level. The analysis of olfactory epithelium, olfactory tract and primary olfactory cortical proteotypes in a multi-disease format will functionally complement the OB dyshomeostasis, increasing our knowledge about the neurodegenerative process across the olfactory axis.
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- 2021
- Full Text
- View/download PDF
9. Alteration in the Cerebrospinal Fluid Lipidome in Parkinson’s Disease: A Post-Mortem Pilot Study
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Joaquín Fernández-Irigoyen, Paz Cartas-Cejudo, Marta Iruarrizaga-Lejarreta, and Enrique Santamaría
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lipids ,cerebrospinal fluid ,Parkinson’s disease ,mass-spectrometry ,lipidomics ,Biology (General) ,QH301-705.5 - Abstract
Lipid metabolism is clearly associated to Parkinson’s disease (PD). Although lipid homeostasis has been widely studied in multiple animal and cellular models, as well as in blood derived from PD individuals, the cerebrospinal fluid (CSF) lipidomic profile in PD remains largely unexplored. In this study, we characterized the post-mortem CSF lipidomic imbalance between neurologically intact controls (n = 10) and PD subjects (n = 20). The combination of dual extraction with ultra-performance liquid chromatography-electrospray ionization quadrupole-time-of-flight mass spectrometry (UPLC-ESI-qToF-MS/MS) allowed for the monitoring of 257 lipid species across all samples. Complementary multivariate and univariate data analysis identified that glycerolipids (mono-, di-, and triacylglycerides), saturated and mono/polyunsaturated fatty acids, primary fatty amides, glycerophospholipids (phosphatidylcholines, phosphatidylethanolamines), sphingolipids (ceramides, sphingomyelins), N-acylethanolamines and sterol lipids (cholesteryl esters, steroids) were significantly increased in the CSF of PD compared to the control group. Interestingly, CSF lipid dyshomeostasis differed depending on neuropathological staging and disease duration. These results, despite the limitation of being obtained in a small population, suggest extensive CSF lipid remodeling in PD, shedding new light on the deployment of CSF lipidomics as a promising tool to identify potential lipid markers as well as discriminatory lipid species between PD and other atypical parkinsonisms.
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- 2021
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10. Data-driven drug repositioning using olfactory omics profiles: challenges and perspectives in neurodegeneration
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Paz Cartas-Cejudo, Adriana Cortés, Mercedes Lachén-Montes, Elena Anaya-Cubero, Joaquín Fernández-Irigoyen, and Enrique Santamaría
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2025
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11. Docosahexaenoic acid ameliorates contextual fear memory deficits in the Tg2576 Alzheimer´s disease mouse model: cellular and molecular correlates
- Author
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Sara Badesso, Paz Cartas-Cejudo, Maria Espelosin, Enrique Santamaria, Mar Cuadrado-Tejedor, Ana Garcia-Osta, Universidad Pública de Navarra. Departamento de Ciencias de la Salud, and Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
- Subjects
DHA ,Pharmaceutical Science ,Alzheimer’s disease ,synapse ,Alzheimer's disease ,Synapse - Abstract
Docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the brain, is essential for successful aging. In fact, epidemiological studies have demonstrated that increased intake of DHA might lower the risk for developing Alzheimer’s disease (AD). These observations are supported by studies in animal models showing that DHA reduces synaptic pathology and memory deficits. Different mechanisms to explain these beneficial effects have been proposed; however, the molecular pathways involved are still unknown. In this study, to unravel the main underlying molecular mechanisms activated upon DHA treatment, the effect of a high dose of DHA on cognitive function and AD pathology was analyzed in aged Tg2576 mice and their wild-type littermates. Transcriptomic analysis of mice hippocampi using RNA sequencing was subsequently performed. Our results revealed that, through an amyloid-independent mechanism, DHA enhanced memory function and increased synapse formation only in the Tg2576 mice. Likewise, the IPA analysis demonstrated that essential neuronal functions related to synaptogenesis, neuritogenesis, the branching of neurites, the density of dendritic spines and the outgrowth of axons were upregulated upon-DHA treatment in Tg2576 mice. Our results suggest that memory function in APP mice is influenced by DHA intake; therefore, a high dose of daily DHA should be tested as a dietary supplement for AD dementia prevention. Grant funding support from the Ministry of Science and Innovation (MINECO) with exp. PID2019-104921RB-I00/MCI/AEI/10.13039/501100011033. Foundation for Applied Medical Research, the University of Navarra (Pamplona, Spain) for financial support and the Asociación de Amigos of the University of Navarra for the grant to S.B.
- Published
- 2023
12. Sex-divergent effects on the NAD+-dependent deacetylase sirtuin signaling across the olfactory-entorhinal-amygdaloid axis in Alzheimer´s and Parkinson´s diseases
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Paz Cartas-Cejudo, Mercedes Lachén-Montes, Isidro Ferrer, Joaquín Fernández-Irigoyen, and Enrique Santamaría
- Abstract
Background: Smell impairment is one of the earliest features in Alzheimer’s (AD) and Parkinson’s diseases (PD). Due to sex differences exist in terms of smell and olfactory structures as well as in the prevalence and manifestation of both neurological syndromes, we have applied olfactory proteomics to favor the discovery of novel sex-biased physio-pathological mechanisms and potential therapeutic targets associated to olfactory dysfunction. Methods: SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) and bioinformatic workflows were applied in 57 postmortem olfactory tracts (OT) derived from non-demented (n=6F/11M), AD (n=4F/13M) and PD (n=7F/16M) subjects. Complementary molecular analyses by Western-blotting were performed in the olfactory bulb (OB), entorhinal cortex (EC) and amygdala areas. Results: 327 and 151 OT differentially expressed proteins (DEPs) were observed in AD women and AD men respectively (35 DEPs in common). Respect to PD, 198 DEPs were identified in PD women whereas 95 DEPs were detected in PD men (20 DEPs in common). This proteome dyshomeostasis induced a disruption in OT protein interaction networks and widespread sex-dependent pathway perturbations in a disease-specific manner, among them Sirtuin (SIRT) signaling. SIRT1, SIRT2, SIRT3 and SIRT5 protein levels unveiled a tangled expression profile across the olfactory-entorhinal-amygdaloid axis, evidencing disease- sex- and brain structure-dependent changes in olfactory protein acetylation. Conclusions: Alteration in the OT proteostasis was more severe in AD than in PD. Moreover, protein expression changes were more abundant in women than men independent of the neurological syndrome. Mechanistically, the tangled SIRT profile observed across the olfactory pathway-associated brain regions in AD and PD indicates differential NAD (+)-dependent deacetylase mechanisms between women and men. All these data shed new light on differential olfactory mechanisms across AD and PD, pointing out that the evaluation of the feasibility of emerging sirtuin-based therapies against neurodegenerative diseases should be considered with caution, including further sex dimension analyses in vivo and in clinical studies.
- Published
- 2022
13. Dysregulated Protein Phosphorylation in a Mouse Model of FTLD-Tau
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Isidro Ferrer, Pol Andrés-Benito, Karina Ausín, Paz Cartas-Cejudo, Mercedes Lachén-Montes, José Antonio del Rio, Joaquín Fernández-Irigoyen, and Enrique Santamaría
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Proteomics ,Mice, Transgenic ,tau Proteins ,General Medicine ,Proteòmica ,Phosphoproteins ,Pathology and Forensic Medicine ,Proteïnes quinases ,Cellular and Molecular Neuroscience ,Disease Models, Animal ,Mice ,Neurology ,Tauopathies ,Protein kinases ,Citosquelet ,Animals ,Neurology (clinical) ,Frontotemporal Lobar Degeneration ,Phosphorylation ,Cytoskeleton - Abstract
The neocortex of P301S mice, used as a model of fronto-temporal lobar degeneration linked to tau mutation (FTLD-tau), and wild-type mice, both aged 9 months, were analyzed with conventional label-free phosphoproteomics and SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 328 corresponding to 524 phosphorylation sites. The majority of dysregulated phosphoproteins, most of them hyperphosphorylated, were proteins of the membranes, synapses, membrane trafficking, membrane vesicles linked to endo- and exocytosis, cytoplasmic vesicles, and cytoskeleton. Another group was composed of kinases. In contrast, proteins linked to DNA, RNA metabolism, RNA splicing, and protein synthesis were hypophosphorylated. Other pathways modulating energy metabolism, cell signaling, Golgi apparatus, carbohydrates, and lipids are also targets of dysregulated protein phosphorylation in P301S mice. The present results, together with accompanying immunohistochemical and Western-blotting studies, show widespread abnormal phosphorylation of proteins, in addition to protein tau, in P301S mice. These observations point to dysregulated protein phosphorylation as a relevant contributory pathogenic component of tauopathies.
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- 2022
14. Dysregulated protein phosphorylation in tauopathy
- Author
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Isidro Ferrer Ferrer, Pol Andrés-Benito, Karina Ausín, Paz Cartas-Cejudo, Mercedes Lachén-Montes, José Antonio del Rio, Joaquín Fernández-Irigoyen, and Enrique Santamaría
- Abstract
The neocortex of P301S mice, used as a model of frontotemporal degeneration linked to tau mutation, and wild-type mice, both aged 9 months, were analyzed with conventional label-free phosphoproteomics and SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 328 corresponding to 524 phosphorylation sites. The majority of dysregulated phosphoproteins, most of them hyper-phosphorylated, were proteins of the membranes, synapses, membrane trafficking, membrane vesicles linked to endo- and exocytosis, cytoplasmic vesicles, and cytoskeleton. Another group was composed of kinases. In contrast, proteins linked to DNA, RNA metabolism, RNA splicing, and protein synthesis were hypo-phosphorylated. Other pathways modulating energy metabolism, cell signalling, Golgi apparatus, carbohydrates, and lipids are also targets of dysregulated protein phosphorylation in P301S mice. The present results, together with accompanying immunohistochemical and western blotting studies, show widespread abnormal phosphorylation of proteins, in addition to protein tau, in P301S mice. These observations point to dysregulated protein phosphorylation as a relevant contributory pathogenic component of tauopathies.
- Published
- 2022
15. Tackling the Biological Meaning of the Human Olfactory Bulb Dyshomeostatic Proteome across Neurological Disorders: An Integrative Bioinformatic Approach
- Author
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Joaquín Fernández-Irigoyen, Mercedes Lachén-Montes, Enrique Santamaría, Paz Cartas-Cejudo, Universidad Pública de Navarra. Departamento de Ciencias de la Salud, Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila, and Gobierno de Navarra / Nafarroako Gobernua
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Proteomics ,Databases, Factual ,Proteome ,Synucleinopathies ,QH301-705.5 ,pathways ,Biology ,Article ,Catalysis ,Progressive supranuclear palsy ,Inorganic Chemistry ,Olfactory bulb ,proteomics ,Alzheimer Disease ,medicine ,Humans ,Physical and Theoretical Chemistry ,Amyotrophic lateral sclerosis ,Neurodegeneration ,Biology (General) ,Pathways ,Molecular Biology ,QD1-999 ,Spectroscopy ,Dementia with Lewy bodies ,Organic Chemistry ,Amyotrophic Lateral Sclerosis ,neurodegeneration ,Computational Biology ,Neurodegenerative Diseases ,Parkinson Disease ,General Medicine ,Frontotemporal lobar degeneration ,medicine.disease ,Olfactory Bulb ,Computer Science Applications ,Chemistry ,medicine.anatomical_structure ,Gene Expression Regulation ,Proteostasis ,Dementia ,Supranuclear Palsy, Progressive ,Nervous System Diseases ,Olfactory epithelium ,Neuroscience ,Olfactory tract ,Transcription Factors - Abstract
Olfactory dysfunction is considered an early prodromal marker of many neurodegenerative diseases. Neuropathological changes and aberrant protein aggregates occur in the olfactory bulb (OB), triggering a tangled cascade of molecular events that is not completely understood across neurological disorders. This study aims to analyze commonalities and differences in the olfactory protein homeostasis across neurological backgrounds with different spectrums of smell dysfunction. For that, an integrative analysis was performed using OB proteomics datasets derived from subjects with Alzheimer’s disease (AD), Parkinson´s disease (PD), mixed dementia (mixD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration (FTLD-TDP43), progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) with respect to OB proteome data from neurologically intact controls. A total of 80% of the differential expressed protein products were potentially disease-specific whereas the remaining 20% were commonly altered across two, three or four neurological phenotypes. A multi-level bioinformatic characterization revealed a subset of potential disease-specific transcription factors responsible for the downstream effects detected at the proteome level as well as specific densely connected protein complexes targeted by several neurological phenotypes. Interestingly, common or unique pathways and biofunctions were also identified, providing novel mechanistic clues about each neurological disease at olfactory level. The analysis of olfactory epithelium, olfactory tract and primary olfactory cortical proteotypes in a multi-disease format will functionally complement the OB dyshomeostasis, increasing our knowledge about the neurodegenerative process across the olfactory axis. This work was funded by grants from the Spanish Ministry of Science, Innovation and Universities (Ref. PID2019-110356RB-I00/ AEI / 10.13039/501100011033 to JF-I and ES) and the Department of Economic and Business Development of the Government of Navarra (Ref. 0011-14112020-000028 to ES).The Proteomics Platform of Navarrabiomed, member of Proteored (PRB3ISCIII), was supported by grant PT17/0019/009, of the PE I+D+I 2013-2016 funded by ISCIII and FEDER to JF. The Clinical Neuroproteomics Unit of Navarrabiomed is member of the Spanish Olfactory Network (ROE) (supported by grant RED2018-102662-T funded by Spanish Ministry of Science and Innovation) and the Global Consortium for Chemosensory Research (GCCR).
- Published
- 2021
16. Combination of Antibody Arrays to Functionally Characterize Dark Proteins in Human Olfactory Neuroepithelial Cells
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Mercedes, Lachén-Montes, Karina, Ausín, Paz, Cartas-Cejudo, Joaquín, Fernández-Irigoyen, and Enrique, Santamaría
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Proteome ,Neuroepithelial Cells ,Protein Array Analysis ,Humans ,Proteins ,Olfactory Bulb ,Antibodies - Abstract
The completion and annotation of the human proteome require the availability of information related to protein function. Currently, more than 1800 human genes constitute the "dark proteome," which include missing proteins, uncharacterized human genes validated at protein level, smORFs, proteins from lncRNAs, or any uncharacterized transcripts. During the last years, different experimental workflows based on multi-omics analyses, bioinformatics, and in vitro and in vivo studies have been promoted by the Human Proteome Project Consortium to enhance the annotation of dark proteins. In this chapter, we describe a method that utilizes recombinant proteins and antibody arrays to establish a straightforward methodology in order to rapidly characterize potential functional features of dark proteins associated to intracellular signaling dynamics and extracellular immune response in human cell cultures. Further validating the method, this workflow was applied to probe changes in the activation patterns of kinases and transcription factors as well as in cytokine production modulated by the dark C1orf128 (PITHD1) protein in human olfactory neuroepithelial cells.
- Published
- 2021
17. Olfactory Bulb Proteomics Reveals Widespread Proteostatic Disturbances in Mixed Dementia and Guides for Potential Serum Biomarkers to Discriminate Alzheimer Disease and Mixed Dementia Phenotypes
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Enrique Santamaría, Ignacio Iñigo-Marco, Mercedes Lachén-Montes, Paz Cartas-Cejudo, Joaquín Fernández-Irigoyen, Universidad Pública de Navarra. Departamento de Ciencias de la Salud, Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila, and Gobierno de Navarra / Nafarroako Gobernua
- Subjects
Proteomics ,Medicine (miscellaneous) ,Biology ,Vascular dementia ,Article ,mixed dementia ,03 medical and health sciences ,Olfactory bulb ,0302 clinical medicine ,proteomics ,medicine ,anatomy_morphology ,030304 developmental biology ,Synucleinopathies ,0303 health sciences ,vascular dementia ,Neuron projection regeneration ,medicine.disease ,LRP1 ,Proteostasis ,Mixed dementia ,olfactory bulb ,Medicine ,Alzheimer's disease ,Neuroscience ,Alzheimer’s disease ,030217 neurology & neurosurgery - Abstract
The most common form of mixed dementia (MixD) is constituted by abnormal protein deposits associated with Alzheimer's disease (AD) that coexist with vascular disease. Although olfactory dysfunction is considered a clinical sign of AD-related dementias, little is known about the impact of this sensorial impairment in MixD at the molecular level. To address this gap in knowledge, we assessed olfactory bulb (OB) proteome-wide expression in MixD subjects (n = 6) respect to neurologically intact controls (n = 7). Around 9% of the quantified proteins were differentially expressed, pinpointing aberrant proteostasis involved in synaptic transmission, nucleoside monophosphate and carbohydrate metabolism, and neuron projection regeneration. In addition, network-driven proteomics revealed a modulation in cell-survival related pathways such as ERK, AKT, and the PDK1-PKC axis. Part of the differential OB protein set was not specific of MixD, also being deregulated across different tauopathies, synucleinopathies, and tardopathies. However, the comparative functional analysis of OB proteome data between MixD and pure AD pathologies deciphered commonalities and differences between both related phenotypes. Finally, olfactory pro-teomics allowed to propose serum Prolow-density lipoprotein receptor-related protein 1 (LRP1) as a candidate marker to differentiate AD from MixD phenotypes. This work was funded by grants from the Spanish Ministry of Science, Innovation and Universities (Ref. PID2019-110356RB-I00/AEI/10.13039/501100011033) and the Department of Economic and Business Development from Government of Navarra (Ref. 0011-1411-2020-000028 to E.S.).
- Published
- 2021
18. Alteration in the Cerebrospinal Fluid Lipidome in Parkinson’s Disease: A Post-Mortem Pilot Study
- Author
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Paz Cartas-Cejudo, Joaquín Fernández-Irigoyen, Marta Iruarrizaga-Lejarreta, Enrique Santamaría, Universidad Pública de Navarra. Departamento de Ciencias de la Salud, and Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
- Subjects
medicine.medical_specialty ,parkinson’s disease ,QH301-705.5 ,Parkinson's disease ,Population ,Mass-spectrometry ,Medicine (miscellaneous) ,Article ,General Biochemistry, Genetics and Molecular Biology ,cerebrospinal fluid ,lipids ,Cerebrospinal fluid ,Internal medicine ,Lipidomics ,medicine ,Biology (General) ,education ,chemistry.chemical_classification ,education.field_of_study ,Lipid metabolism ,Lipidome ,mass-spectrometry ,Lipids ,Sphingolipid ,Endocrinology ,chemistry ,lipidomics ,lipids (amino acids, peptides, and proteins) ,Sphingomyelin ,Polyunsaturated fatty acid - Abstract
Lipid metabolism is clearly associated to Parkinson’s disease (PD). Although lipid homeostasis has been widely studied in multiple animal and cellular models, as well as in blood derived from PD individuals, the cerebrospinal fluid (CSF) lipidomic profile in PD remains largely unexplored. In this study, we characterized the post-mortem CSF lipidomic imbalance between neurologically intact controls (n = 10) and PD subjects (n = 20). The combination of dual extraction with ultra-performance liquid chromatography-electrospray ionization quadrupole-time-of-flight mass spectrometry (UPLC-ESI-qToF-MS/MS) allowed for the monitoring of 257 lipid species across all samples. Complementary multivariate and univariate data analysis identified that glycerolipids (mono-, di-, and triacylglycerides), saturated and mono/polyunsaturated fatty acids, primary fatty amides, glycerophospholipids (phosphatidylcholines, phosphatidylethanolamines), sphingolipids (ceramides, sphingomyelins), N-acylethanolamines and sterol lipids (cholesteryl esters, steroids) were significantly increased in the CSF of PD compared to the control group. Interestingly, CSF lipid dyshomeostasis differed depending on neuropathological staging and disease duration. These results, despite the limitation of being obtained in a small population, suggest extensive CSF lipid remodeling in PD, shedding new light on the deployment of CSF lipidomics as a promising tool to identify potential lipid markers as well as discriminatory lipid species between PD and other atypical parkinsonisms.
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- 2021
19. Contributors
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Angela Marie Abbatecola, Ahmed Abdellatif, Shameemah Abrahams, Anne Almey, Sevilhan Artan, Hamdino Attia, Karina Ausin, Soraya Bardien, Martin Bareš, Minke Bekker, Amogh Belagodu, Antonello Bellomo, Olga A. Belova, Sebastián Beltrán-Castillo, Agata Białecka-De¸bek, Karina Henrique Binda, Daniel M. Blumberger, Mariangela Boccardi, Virginia Boccardi, Benjamin D. Boros, Luca Anna Bors, Alessandro Bortolami, Daniel C. Bowie, Francesca Bruno, Paulo Caramelli, G.P. Cardona-Gómez, Jonathan Carr, Paz Cartas-Cejudo, Gemma Casadesus, Grace M. Clements, Katelyn Cuttler, Antonio Daniele, Zafiris J. Daskalakis, Vittorio Dibello, Michelino Di Rosa, Velia D’Agata, Agata Grazia D’Amico, Andre du Toit, Mehrangiz Ebrahimi-Mameghani, B.J.L. Eggen, Okobi Ekpo, Franciska Erdő, Kirk I. Erickson, Ebru Erzurumluoglu Gokalp, Kurt A. Escobar, Jaime Eugenín, Monica Fabiani, Mahitab Farghali, Concetta Federico, Joaquín Fernández-Irigoyen, Federica Ferrari, Isidro Ferrer, Pavel Filip, Vanêssa Gomes Fraga, Mitsuhiro Furuse, Roberto Galvez, Samantha L. Gardener, Nicole J. Gervais, Gianluigi Giannelli, Laura Gil, Karina Braga Gomes, Andrea González-Morales, Stuart L. Graham, Gabriele Gratton, Antonio Greco, Andrey Grigoriev, Yian Gu, Lingyu Guan, Joshua M. Gulley, Vivek K. Gupta, Jeremy H. Herskowitz, Shozo Jinno, Lars Stiernman Jonasson, Mariona Jové, Shuo Kang, Michy P. Kelly, Ryuta Kinno, Maria G. Knyazeva, Joanne Koh, Marisa Koini, Yulia K. Komleva, Mercedes Lachén-Montes, Maddalena La Montagna, Anne Marlene Landau, Fulvio Lauretani, Ran Li, Yuandong Li, Xuan Li, Jennifer I. Lissemore, Ben Loos, Olga L. Lopatina, Madia Lozupone, Andrew G. MacLean, Tando Maduna, Marcello Maggio, Alireza Majdi, Hanani Abdul Manan, Raffaele Marfella, Grazia Maugeri, Naroa Mendizuri, Megan Mey, Kiyohito Mizutani, Claudio Molinari, Vera Morsanuto, Natalia Mota-Martorell, Sheeja Navakkode, Gina Nicoll, Kenjiro Ono, Demet Ozbabalik Adapinar, Reinald Pamplona, Francesco Panza, Tiffany A. Peterson, Irene Pradas, Victor R. Preedy, Stephanie R. Rainey-Smith, Caroline Cristiano Real, Catarina Rendeiro, Justin S. Rhodes, Georgia A.F. Rogerson, Sara Ruga, Salvatore Saccone, Saeed Sadigh-Eteghad, Vladimir V. Salmin, Alla B. Salmina, Mahzad Sanayei, Cristina Sanfilippo, Enrique Santamaría, Rodolfo Sardone, Heide Schatten, Davide Seripa, Federico Sesti, Ting Shen, Vincenzo Solfrizzi, Tuck Wah Soong, Anna Starnawska, Nicklas Heine Staunstrup, Chelsea Stillman, Valentina Sturiale, Yoshimi Takai, Dennis A. Turner, Francesca Uberti, Elnaz Vaghef-Mehrabany, Leila Vaghef-Mehrabany, Trisha A. VanDusseldorp, Roberto Federico Villa, J. Villamil-Ortiz, Rommy von Bernhardi, Ruikang K. Wang, Lauren Wengle, Yu-Chien Wu, Noorazrul Azmie Yahya, Jun Yamada, Wei Yang, Yuyi You, Ahmad Nazlim Yusoff, and Jing Zhai
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- 2021
20. The prohibitin complex in aging and neurodegeneration
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Naroa Mendizuri, Karina Ausín, Andrea González-Morales, Mercedes Lachén-Montes, Joaquín Fernández-Irigoyen, Paz Cartas-Cejudo, and Enrique Santamaría
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Cell type ,biology ,Neurodegeneration ,medicine ,Olfaction ,Prohibitin ,Proteomics ,medicine.disease ,biology.organism_classification ,Caenorhabditis elegans ,Cellular localization ,Olfactory bulb ,Cell biology - Abstract
Prohibitins are ubiquitous proteins involved in multiple biological functions depending on the cell type and their cellular localization. Prohibitins exert an essential role in the maintenance of mitochondrial structure and functionality. Besides alterations observed in metabolic and oncogenic processes, an imbalance in prohibitin system triggers mitochondrial defects leading to lifespan reduction in yeast and Caenorhabditis elegans, and impairments in mitochondrial homeostasis in neurological disorders such as Parkinson disease. In general, the aging and neurodegenerative processes are accompanied by a dysfunction of the sense of smell. Recent advances in olfactory proteomics have allowed to characterize a disruption of prohibitin subunits at the level of the olfactory bulb, unveiling prohibitin complex as a differential driver of neurodegeneration across different proteinopathies at olfactory level.
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- 2021
21. Combination of Antibody Arrays to Functionally Characterize Dark Proteins in Human Olfactory Neuroepithelial Cells
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Enrique Santamaría, Paz Cartas-Cejudo, Mercedes Lachén-Montes, Joaquín Fernández-Irigoyen, and Karina Ausín
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0303 health sciences ,030302 biochemistry & molecular biology ,Computational biology ,Biology ,In vitro ,Neuroepithelial cell ,03 medical and health sciences ,Proteome ,Extracellular ,Human proteome project ,Human genome ,Transcription factor ,Intracellular ,030304 developmental biology - Abstract
The completion and annotation of the human proteome require the availability of information related to protein function. Currently, more than 1800 human genes constitute the "dark proteome," which include missing proteins, uncharacterized human genes validated at protein level, smORFs, proteins from lncRNAs, or any uncharacterized transcripts. During the last years, different experimental workflows based on multi-omics analyses, bioinformatics, and in vitro and in vivo studies have been promoted by the Human Proteome Project Consortium to enhance the annotation of dark proteins. In this chapter, we describe a method that utilizes recombinant proteins and antibody arrays to establish a straightforward methodology in order to rapidly characterize potential functional features of dark proteins associated to intracellular signaling dynamics and extracellular immune response in human cell cultures. Further validating the method, this workflow was applied to probe changes in the activation patterns of kinases and transcription factors as well as in cytokine production modulated by the dark C1orf128 (PITHD1) protein in human olfactory neuroepithelial cells.
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- 2021
22. 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
- Full Text
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