Nahuai Badiola - Academia.edu (original) (raw)

Papers by Nahuai Badiola

PLOS ONE, 2015

A key element to delineate the biology of individual tumors is the regulation of apoptosis. In th... more A key element to delineate the biology of individual tumors is the regulation of apoptosis. In this work, we functionally characterize two breast cancer associated genes, the proteasome 26S subunit ATPase 3 interacting protein (PSMC3IP) and the epithelial-stromal interaction 1 (EPSTI1), to explore their potential apoptotic role in breast cancer. We first explore the existence of direct physical interactions with annotated BC-apoptotic genes. Based on the generated interaction network, we examine several apoptotic markers to determine the effect of PSMC3IP and EPSTI1 gene expression modulation in two different human breast cancer cell lines to suggest potential molecular mechanisms to unveil their role in the disease. Our results show that PSMC3IP and EPSTI1 are able to modulate the extrinsic apoptotic pathway in estrogen receptor positive and triple negative breast cancer cell lines, highlighting them as potential therapeutic targets.

Journal of Neuroscience, 2007

Death receptors (DRs) and their ligands are expressed in developing nervous system. However, neur... more Death receptors (DRs) and their ligands are expressed in developing nervous system. However, neurons are generally resistant to death induction through DRs and rather their activation promotes neuronal outgrowth and branching. These results suppose the existence of DRs antagonists expressed in the nervous system. Fas apoptosis inhibitory molecule (FAIM S ) was first identified as a Fas antagonist in B-cells. Soon after, a longer alternative spliced isoform with unknown function was identified and named FAIM L . FAIM S is widely expressed, including the nervous system, and we have shown previously that it promotes neuronal differentiation but it is not an anti-apoptotic molecule in this system. Here, we demonstrate that FAIM L is expressed specifically in neurons, and its expression is regulated during the development. Expression could be induced by NGF through the extracellular regulated kinase pathway in PC12 (pheochromocytoma cell line) cells. Contrary to FAIM S , FAIM L does not increase the neurite outgrowth induced by neurotrophins and does not interfere with nuclear factor B pathway activation as FAIM S does. Cells overexpressing FAIM L are resistant to apoptotic cell death induced by DRs such as Fas or tumor necrosis factor R1. Reduction of endogenous expression by small interfering RNA shows that endogenous FAIM L protects primary neurons from DR-induced cell death. The detailed analysis of this antagonism shows that FAIM L can bind to Fas receptor and prevent the activation of the initiator caspase-8 induced by Fas. In conclusion, our results indicate that FAIM L could be responsible for maintaining initiator caspases inactive after receptor engagement protecting neurons from the cytotoxic action of death ligands.

PLoS ONE, 2011

Background: The simultaneous accumulation of different misfolded proteins in the central nervous ... more Background: The simultaneous accumulation of different misfolded proteins in the central nervous system is a common feature in many neurodegenerative diseases. In most cases, co-occurrence of abnormal deposited proteins is observed in different brain regions and cell populations, but, in some instances, the proteins can be found in the same cellular aggregates. Co-occurrence of tau and a-synuclein (a-syn) aggregates has been described in neurodegenerative disorders with primary deposition of a-syn, such as Parkinson's disease and dementia with Lewy bodies. Although it is known that tau and a-syn have pathological synergistic effects on their mutual fibrillization, the underlying biological effects remain unclear.

PLoS ONE, 2013

A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-b (Ab)... more A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-b (Ab) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by band c-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Ab production in AD cellular and animal models. We found that lansoprazole enhances Ab37, Ab40 and Ab42 production and lowers Ab38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Ab40 levels in brain, indicating that lansoprazole may also exacerbate Ab production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.

Neurobiology of Disease, 2009

TNF-α has been reported to be relevant in stroke-induced neuronal death. However the precise func... more TNF-α has been reported to be relevant in stroke-induced neuronal death. However the precise function of TNF-α in brain ischemia remains controversial since there are data supporting either a detrimental or a protective effect. Here we show that TNF-α is released after oxygen-glucose deprivation (OGD) of cortical cultures and is a major contributor to the apoptotic death observed without affecting the OGD-mediated necrotic cell death. In this paradigm, apoptosis depends on TNF-α-induced activation of caspase-8 and -3 without affecting the activation of caspase-9. By using knock-out mice for TNF-α receptor 1, we show that the activation of both caspase-3 and -8 by TNF-α is mediated by TNF-α receptor 1. The pro-apoptotic role of TNFα in OGD is restricted to neurons and microglia, since astrocytes do not express either TNF-α or TNF-α receptor 1. Altogether, these results show that apoptosis of cortical neurons after OGD is mediated by TNF-α/ TNF-α receptor 1.

Molecular Biology of the Cell, 2009

Here, we examined the eventual role of BMPs on the survival of these neurons. Lack of depolarizat... more Here, we examined the eventual role of BMPs on the survival of these neurons. Lack of depolarization causes CGC death by apoptosis in vivo, a phenomenon that is mimicked in vitro by deprivation of high potassium in cultured CGCs. We have found that BMP-6, but not BMP-7, is able to block low potassium-mediated apoptosis in CGCs. The neuroprotective effect of BMP-6 is not accompanied by an increase of Smad translocation to the nucleus, suggesting that the canonical pathway is not involved. By contrast, activation of the MEK/ERK/CREB pathway by BMP-6 is necessary for its neuroprotective effect, which involves inhibition of caspase activity and an increase in Bcl-2 protein levels. Other pathways involved in the regulation of CGC survival, such as the c-Jun terminal kinase and the phosphatidylinositol 3-kinase (PI3K)-Akt/PKB, were not affected by BMP-6. Moreover, failure of BMP-7 to activate the MEK/ ERK/CREB pathway could explain its inability to protect CGCs from low potassium-mediated apoptosis. Thus, this study demonstrates that BMP-6 acting through the noncanonical MEK/ERK/CREB pathway plays a crucial role on CGC survival. ‡ Present address:

Journal of Neurochemistry, 2014

Autosomal-dominant Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (ADAD) is ... more Autosomal-dominant Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studying the mechanisms underlying these mutations can provide insight into the pathways that lead to AD pathology. The majority of biochemical studies on APP mutations to-date have focused on comparing mechanisms between mutations at different codons. It has been assumed that amino acid position is a major determinant of protein dysfunction and clinical phenotype. However, the differential effect of mutations at the same codon has not been sufficiently addressed. In the present study we compared the effects of the aggressive ADAD-associated APP I716F mutation with I716V and I716T on APP processing in human neuroglioma and CHO-K1 cells. All APP I716 mutations increased the ratio of Aβ42/40 and changed the product line preference of γ-secretase towards Aβ38 production. In addition, the APP I716F mutation impaired the ε-cleavage and the fourth cleavage of γ-secretase and led to abnormal APP β-CTF accumulation at the plasma membrane. Taken together, these data indicate that APP mutations at the same codon can induce diverse abnormalities in APP processing, some resembling PSEN1 mutations. These differential effects could explain the clinical differences observed among ADAD patients bearing different APP mutations at the same position. The amyloid precursor protein (APP) I716F mutation is associated with autosomal dominant Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease with the youngest age-at-onset for the APP locus. Here, we describe that this mutation, when compared to two other familial Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease mutations at the same codon (I716V and I716T), interfered distinctly with γ-secretase cleavage. While all three mutations direct γ-secretase cleavage towards the 48→38 production line, the APP I716F mutation also impaired the ε-cleavage and the fourth cleavage of γ-secretase, resembling a PSEN1 mutation. These features may contribute to the aggressiveness of this mutation.

Journal of Biological Chemistry, 2012

The mechanism involved in activity-dependent survival of neurons in the central nervous system is... more The mechanism involved in activity-dependent survival of neurons in the central nervous system is not fully understood. Results: Nurr1 is involved in excitatory transmission-dependent survival of glutamatergic neurons by acting downstream CREB and upstream of BDNF. Conclusion: Nurr1 activation mediates activity-dependent survival of glutamatergic neurons. Significance: A novel function of Nurr1 in activity-dependent survival of glutamatergic neurons is reported.

CNS & Neurological Disorders - Drug Targets, 2010

Tauopathies are neurodegenerative diseases characterized by insoluble hyperphosphorylated deposit... more Tauopathies are neurodegenerative diseases characterized by insoluble hyperphosphorylated deposits of the microtubuleassociated protein tau in the central nervous system. In these disorders, tau is believed to cause neurodegeneration and neuronal loss due to the loss of function of the normal protein, and/or the gain of toxic properties by generating multimeric species. The obstacles found in amyloid-based therapies in Alzheimer's disease, the most common tauopathy, have stimulated the search for alternative targets, including tau. In this article, we review the strategies aimed at reducing tau phosphorylation and aggregation as a target for drug intervention in tauopathies.

Cell Research, 2008

Bcl-x L controls the biological response to TNF-α 1020 npg Upon activation, tumor necrosis factor... more Bcl-x L controls the biological response to TNF-α 1020 npg Upon activation, tumor necrosis factor alpha (TNF-α) receptor can engage apoptotic or survival pathways. Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death. It is believed that this sensitization is due to the transcriptional blockade of genes regulated by NF-κB. Nevertheless, such evidence has remained elusive in the nervous system. Here, we show that TNF-α cannot normally induce apoptosis in PC12 cells or cortical neurons. However, cells treated with Actinomycin D (ActD) become susceptible to TNF-α-induced cell death through the activation of caspase-8, generation of tBid and activation of caspase-9 and -3. Analysis of several proteins involved in TNF-α receptor signaling showed no significant downregulation of NF-κB target genes, such as IAPs or FLIP, under such conditions. However, Bcl-x L protein levels, but not those of Bcl-2, Bax and Bak, are reduced by ActD or TNF-α/ ActD treatments. Moreover, Bcl-x L overexpression fully protects cells against TNF-α/ActD-induced cell death. When endogenous levels of Bcl-x L are specifically downregulated by lentiviral-based RNAi, cells no longer require ActD to be sensitive to TNF-α-triggered apoptosis. Furthermore, Bcl-x L downregulation does not affect TNF-α-mediated NF-κB activation. Altogether, our results demonstrate that Bcl-x L , and not Bcl-2, FLIP or IAPs, acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-α-induced apoptosis in an NF-κB-independent manner.

BioEssays, 2012

Here we postulate that the adapter protein evolutionarily conserved signalling intermediate in To... more Here we postulate that the adapter protein evolutionarily conserved signalling intermediate in Toll pathway (ECSIT) might act as a molecular sensor in the pathogenesis of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD). Based on the analysis of our AD-associated protein interaction network, ECSIT emerges as an integrating signalling hub that ascertains cell homeostasis by the specific activation of protective molecular mechanisms in response to signals of amyloid-beta or oxidative damage. This converges into a complex cascade of patho-physiological processes. A failure to repair would generate severe mitochondrial damage and ultimately activate pro-apoptotic mechanisms, promoting synaptic dysfunction and neuronal death. Further support for our hypothesis is provided by increasing evidence of mitochondrial dysfunction in the disease etiology. Our model integrates seemingly controversial hypotheses for familial and sporadic forms of AD and envisions ECSIT as a biomarker to guide future therapies to halt or prevent AD.

Alzheimer's & Dementia, 2012

Alzheimer's & Dementia, 2011

transcription of genes involved in protein quality control and degradation pathways as well as fl... more transcription of genes involved in protein quality control and degradation pathways as well as fly homologue of Aß degrading enzymes. In addition, genes known to be induced by stresses were up regulated by Sin3A knockdown, and overexpression of these genes suppressed Aß42 toxicity without altering Aß accumulation. We further demonstrated that these genes were up regulated in human neuroblastoma SH-SY5Y cells treated with HDAC inhibitors. Conclusions: Our results indicate that multiple mechanisms underlie protective effects of inhibition of Sin3A/HDACs activity against Aß42induced toxicity.

Acta Neuropathologica, 2013

Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been cri... more Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been critical to support the amyloid cascade hypothesis of Alzheimer disease (AD), the basis for the current development of amyloid-based disease-modifying therapies in sporadic AD (SAD). However, whether the pathological changes in APP processing in the CNS in ADAD are similar to those observed in SAD remains unclear. In this study, we measured b-site APP-cleaving enzyme (BACE) protein levels and activity, APP and APP C-terminal fragments in brain samples from subjects with ADAD carrying APP or PSEN1 mutations (n = 18), patients with SAD (n = 27) and agematched controls (n = 22). We also measured sAPPb and BACE protein levels, as well as BACE activity, in CSF from individuals carrying PSEN1 mutations (10 mutation carriers and 7 non-carrier controls), patients with SAD (n = 32) and age-matched controls (n = 11). We found that in the brain, the pattern in ADAD was characterized by an increase in APP b-C-terminal fragment (b-CTF) levels despite no changes in BACE protein levels or activity. In contrast, the pattern in SAD in the brain was mainly characterized by an increase in BACE levels and activity, with less APP b-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPPb levels. Taken together, these data suggest that the physiopathological events underlying the chronic Ab production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD.

Cell Death and Disease, 2011

Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reti... more Disturbance of calcium homeostasis and accumulation of misfolded proteins in the endoplasmic reticulum (ER) are considered contributory components of cell death after ischemia. However, the signal-transducing events that are activated by ER stress after cerebral ischemia are incompletely understood. In this study, we show that caspase-12 and the PERK and IRE pathways are activated following oxygen-glucose deprivation (OGD) of mixed cortical cultures or neonatal hypoxia-ischemia (HI). Activation of PERK led to a transient phosphorylation of eIF2a, an increase in ATF4 levels and the induction of gadd34 (a subunit of an eIF2adirected phosphatase). Interestingly, the upregulation of ATF4 did not lead to an increase in the levels of CHOP. Additionally, IRE1 activation was mediated by the increase in the processed form of xbp1, which would be responsible for the observed expression of edem2 and the increased levels of the chaperones GRP78 and GRP94. We were also able to detect caspase-12 proteolysis after HI or OGD. Processing of procaspase-12 was mediated by NMDA receptor and calpain activation. Moreover, our data suggest that caspase-12 activation is independent of the unfolded protein response activated by ER stress.