Biology subjects

Santamaria, E.

Publications and source records attributed to Santamaria, E..

5 recordsLinked to original sources

bioRxiv2023

Neuropathological stage-dependent proteome mapping of the olfactory tract in Alzheimer's disease: From early olfactory-related omics signatures to computational repurposing of drug candidates

Alzheimers disease (AD) is the most common form of dementia, characterized by an early olfactory dysfunction, progressive memory loss and behavioral deterioration. Albeit substantial progress has been made in characterizing AD-associated molecular and cellular events, there is an unmet clinical need for new therapies. In this work, olfactory tract proteotyping performed in controls and AD subjects (n=17/group) showed a Braak stage-dependent proteostatic impairment accompanied by the progressive modulation of amyloid precursor protein (APP) and tau functional interactomes. To implement a computational repurposing of drug candidates with capacity to reverse early AD-related olfactory omics signatures, we generated a consensual olfactory omics signatures (OMSs) database compiling differential omics datasets obtained by mass-spectrometry or RNA-sequencing derived from initial AD across the olfactory axis. Using the Connectivity Map (CMAP)-based drug repurposing approach, PKC, EGFR, Aurora kinase, Glycogen synthase kinase and CDK inhibitors were the top pharmacologic classes capable to restore multiple OMSs, whereas compounds with targeted activity to inhibit PI3K, IGF-1, microtubules and PLK represented a family of drugs with detrimental potential to induce olfactory AD-associated gene expression changes. In-vitro validation assays revealed that pretreatment of human neuron-like SH-SY5Y cells with the EGFR inhibitor AG-1478 showed a neuroprotective effect against hydrogen peroxide-induced damage while the pretreatment with the Aurora kinase inhibitor Reversine reduced amyloid-beta (A{beta})-induced neurotoxicity. Taken together, our data pointed out that olfactory omics signatures may be useful as substrates for drug repurposing to propose novel neuroprotective treatments against AD. STATEMENTSO_ST_ABSData availability statementC_ST_ABSMass-spectrometry data and search results files were deposited in the Proteome Xchange Consortium via the JPOST partner repository (https://repository.jpostdb.org) with the identifier PXD038061 for ProteomeXchange and JPST001921 for jPOST (for reviewers: https://repository.jpostdb.org/preview/1400199357636bce4231af5 Access key: 8609). The data supporting the findings of this study are available in Supplementary Material. Raw data are available from the corresponding author, upon reasonable request. Funding statementThis work was funded by grants from the Spanish Ministry of Science, Innovation and Universities (Ref. PID2019-110356RB-I00/AEI/10.13039/501100011033) to J.F.-I. and E.S. and the Department of Economic and Business Development from Government of Navarra (Ref. 0011-1411-2023-000028 to E.S.). PC-C was supported by a predoctoral fellowship from the Public University of Navarra (UPNA). ML-M is supported by a postdoctoral fellowship from Miguel Servet Foundation-Navarrabiomed. EA-C is supported by "Programa MRR Investigo 2023" in the framework of the European Union recovery and resilience facility. Conflict of interest disclosureAuthors declare that they have no conflicts of interest/financial disclosures. Ethics approval and patient consent statementAccording to the Spanish Law 14/2007 of Biomedical Research, inform written consent from several Spanish Neurological Tissue Banks was obtained for research purposes from relatives of subjects included in this study. According to the Declaration of Helsinki, all assessments, post-mortem evaluations, and experimental procedures were previously approved by the Clinical Ethics Committee of Navarra Health Service (Study code: PI_2019/108).

neuroscience↗

bioRxiv2023

4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy

Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. To identify factors that contribute to these differences, we performed proteomic and spatial transcriptomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity. These observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.

neuroscience↗

bioRxiv2022

GLUT1 ablation in astrocytes paradoxically improves central and peripheral glucose metabolism via enhanced insulin-stimulated ATP release

Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e. GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 ablation (GLUT11'GFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Importantly, GLUT11'GFAP mice did not present cognitive alterations. Mechanistically, we observed that GLUT1-ablated astrocytes exhibited increased insulin receptor-dependent ATP release, and both astrocyte insulin signalling and brain purinergic signalling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its ablation triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis and cognitive function.

neuroscience↗

bioRxiv2022

Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions

One of the most common symptoms in COVID-19 is a sudden loss of smell. SARS-CoV-2 has been detected in the olfactory bulb (OB) from animal models and sporadically in COVID-19 patients. To decipher the specific role over the SARS-CoV-2 proteome at olfactory level, we characterized the in-depth molecular imbalance induced by the expression of GFP-tagged SARS-CoV-2 structural proteins (M, N, E, S) on mouse OB cells. Transcriptomic and proteomic trajectories uncovered a widespread metabolic remodeling commonly converging in extracellular matrix organization, lipid metabolism and signaling by receptor tyrosine kinases. The molecular singularities and specific interactome expression modules were also characterized for each viral structural factor. The intracellular molecular imbalance induced by each SARS-CoV-2 structural protein was accompanied by differential activation dynamics in survival and immunological routes in parallel with a differentiated secretion profile of chemokines in OB cells. Machine learning through a proteotranscriptomic data integration uncovered TGF-beta signaling as a confluent activation node by the SARS-CoV-2 structural proteome. Taken together, these data provide important avenues for understanding the multifunctional immunomodulatory properties of SARS-CoV-2 M, N, S and E proteins beyond their intrinsic role in virion formation, deciphering mechanistic clues to the olfactory inflammation observed in COVID-19 patients.

systems biology↗

bioRxiv2020

HUMAN PANCREATIC CANCER CELLS UNDERGO PROFOUND METABOLIC REPROGRAMMING TOWARDS CELLULAR STEMNESS AS ADAPTATION TO INHIBITION OF THE AKT PATHWAY

Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression. The mechanisms of adaptation to long-term silencing of AKT isoforms of pancreatic cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism, and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG up-regulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.

cancer biology↗