Open Access
Interrogating the epigenome to unveil the secrets of neurodegeneration: promising epigenetic therapies
(SciTech Central, 2016-07-25) Teijido Hermida, Óscar; Cacabelos, Ramón; Ciencias de la Salud; Osasun Zientziak
According to the WHO, cerebrovascular and neurodegenerative disorders affect one billion people around the world. Pathological phenotypes of neurodegeneration result from a combination of genomic, epigenomic, metabolic, and environmental factors, which hinder their treatment. Indeed, current FDA-approved conventional drugs used for treatment of neurodegenerative disorders provide very little beneficial effects, or, at best, reduce the pathological symptoms but do not detain disease progression. Furthermore, the unacceptable side effects of most of these treatments make them unsuitable for chronic treatments. One of the main reasons for this historical setback correlates with the poor knowledge about the molecular mechanisms of these pathologies, which results in the inappropriate drug target selection. Genetic components did not fully explain the mechanisms of those diseases. Furthermore, most treatments target symptomatic features of disease but they are not antipathogenic. During the last 15 years, the study of the role of the epigenetic machinery on gene regulation opens new and promising perspectives for a more accurate and effective treatment. Aberrant alterations in the epigenetic machinery result in dysregulation of gene expression at different levels in pathological conditions compared to healthy controls. The epigenetic approach allows the identification of key pathological targets in complex disorders that cannot be detected using genetic-based methods. Many of these epigenetic targets may be detected in early asymptomatic stages of the disease, which facilitates its treatment. Furthermore, the reversibility and potential restoring of epigenetic aberrations, unlike genetic mutations, sited epigenetic-based therapy as a promising tool to treat those complex disorders. This manuscript reviews the main epigenetic mechanisms involved in the most relevant neurodegenerative disorders nowadays, as well as the potential epigenetic-based drugs currently used in clinical trials for treatment of those disorders and future perspectives.
Open Access
Pharmacogenomics and epigenomics of age-related neurodegenerative disorders: strategies for drug development
(Royal Society of Chemistry, 2017) Cacabelos, Ramón; Carril, Juan Carlos; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
Open Access
Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects
(IRL Press at Oxford University Press, 2008-08-30) Duarri, Anna; Teijido Hermida, Óscar; López-Hernández, Tania; Scheper, Gert C.; Barriere, Herve; Boor, Ilja; Aguado, Fernando; Zorzano, Antonio; Palacín, Manuel; Martínez, Albert; Lukacs, Gergely L.; Van der Knaap, Marjo S.; Nunes, Virginia; Estévez, Raúl; Ciencias de la Salud; Osasun Zientziak
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy, most often caused by mutations in the MLC1 gene. MLC1 is an oligomeric plasma membrane (PM) protein of unknown function expressed mainly in glial cells and neurons. Most disease-causing missense mutations dramatically reduced the total and PM MLC1 expression levels in Xenopus oocytes and mammalian cells. The impaired expression of the mutants was verified in primary cultures of rat astrocytes, as well as human monocytes, cell types that endogenously express MLC1, demonstrating the relevance of the tissue culture models. Using a combination of biochemical, pharmacological and imaging methods, we also demonstrated that increased endoplasmatic reticulum-associated degradation and endo-lysosomal-associated degradation can contribute to the cell surface expression defect of the mutants. Based on these results, we suggest that MLC1 mutations reduce protein levels in vivo. Since the expression defect of the mutants could be rescued by exposing the mutant-protein expressing cells to low temperature and glycerol, a chemical chaperone, we propose that MLC belongs to the class of conformational diseases. Therefore, we suggest the use of pharmacological strategies that improve MLC1 expression to treat MLC patients.
Open Access
Characterization of the common genetic variation in the spanish population of Navarre
(MDPI, 2024) Maíllo Ruiz de Infante, Alberto; Huergo, Estefanía; Apellániz Ruiz, María Valvanera; Urrutia Lafuente, Edurne; Miranda, María; Salgado Garrido, Josefa; Pasalodos Sánchez, Sara; Delgado-Mora, Luna; Teijido Hermida, Óscar; Goicoechea, Ibai; Carmona, Rosario; Pérez-Florido, Javier; Aquino, Virginia; López-López, Daniel; Peña-Chilet, María; Beltrán, Sergi; Dopazo, Joaquín; Lasa Uzcudun, Íñigo; Beloqui, Juan José; NAGEN-Scheme; Alonso Sánchez, Ángel Miguel; Gómez-Cabrero, David; Ciencias de la Salud; Osasun Zientziak
Large-scale genomic studies have significantly increased our knowledge of genetic variability across populations. Regional genetic profiling is essential for distinguishing common benign variants from disease-causing ones. To this end, we conducted a comprehensive characterization of exonic variants in the population of Navarre (Spain), utilizing whole genome sequencing data from 358 unrelated individuals of Spanish origin. Our analysis revealed 61,410 biallelic single nucleotide variants (SNV) within the Navarrese cohort, with 35% classified as common (MAF > 1%). By comparing allele frequency data from 1000 Genome Project (excluding the Iberian cohort of Spain, IBS), Genome Aggregation Database, and a Spanish cohort (including IBS individuals and data from Medical Genome Project), we identified 1069 SNVs common in Navarre but rare (MAF ≤ 1%) in all other populations. We further corroborated this observation with a second regional cohort of 239 unrelated exomes, which confirmed 676 of the 1069 SNVs as common in Navarre. In conclusion, this study highlights the importance of population-specific characterization of genetic variation to improve allele frequency filtering in sequencing data analysis to identify disease-causing variants.
Open Access
The cytosolic domain of human Tom22 modulates human Bax mitochondrial translocation and conformation in yeast
(Elsevier, 2012) Renault, Thibaud T.; Grandier-Vazeille, Xavier; Arokium, Hubert; Velours, Gisèle; Camougrand, Nadine; Priault, Muriel; Teijido Hermida, Óscar; Dejean, Laurent M.; Manon, Stéphen; Ciencias de la Salud; Osasun Zientziak
The role of the mitochondrial protein receptor Tom22p in the interaction of pro-apoptotic protein Bax with yeast mitochondria was investigated. Co-immunoprecipitation assays showed that human Bax interacted with different TOM subunits, including Tom22p. Expression of the cytosolic receptor domain of human Tom22 increased Bax mitochondrial localization, but decreased the proportion of active Bax. BN-PAGE showed that the cytosolic domain of Tom22 interfered with the oligomerization of Bax. These data suggest that the interaction with the cytosolic domain of Tom22 helps Bax to acquire a conformation able to interact with the outer mitochondrial membrane.
Open Access
Epigenomics and proteomics of brain disorders
(SciTech Central, 2017-11-30) Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan Carlos; Teijido Hermida, Óscar; Ciencias de la Salud; Osasun Zientziak
Epigenomic mechanisms (DNA methylation, chromatin remodeling/histone modifications, miRNA regulation) are involved in the transcriptional and post-translational regulation of genes in physiological and pathological conditions leading to potentially reversible phenotypes. Mutations in the genes encoding elements of the epigenetic machinery cause epigenetic Mendelian disorders. Epigenetic aberrations contribute to the pathogenesis of neurodevelopmental, imprinting, neuropsychiatric, and age-related neurodegenerative disorders. Some brain disorders exhibit proteoepigenomic changes resulting from primary genomic traits and/or secondary epigenetic events which induce pathogenic (structural, functional, conformational) changes in key proteins. Proteomic biomarkers and epigenomic signatures may help in the prediction, early diagnosis, and prognosis of CNS disorders. Epigenetic drug discovery, application of pharmacoepigenomic procedures for personalized therapeutics, novel approaches to decode and resolve drug resistance, and targeting miRNAs in prevention and treatment of brain disorders are promising areas of future development.
Open Access
MAC and Bcl-2 family proteins conspire in a deadly plot
(Elsevier, 2010-01-18) Dejean, Laurent M.; Ryu, Shin-Young; Martínez-Caballero, Sonia; Teijido Hermida, Óscar; Peixoto, Pablo M.; Kinnally, Kathleen W.; Ciencias de la Salud; Osasun Zientziak
Apoptosis is an elemental form of programmed cell death; it is fundamental to higher eukaryotes and essential to mechanisms controlling tissue homeostasis. Apoptosis is also involved in many pathologies including cancer, neurodegenerative diseases, aging, and infarcts. This cell death program is tightly regulated by Bcl-2 family proteins by controlling the formation of the mitochondrial apoptosis-induced channel or MAC. Assembly of MAC corresponds to permeabilization of the mitochondrial outer membrane, which is the so called commitment step of apoptosis. MAC provides the pathway through the mitochondrial outer membrane for the release of cytochrome c and other pro-apoptotic factors from the intermembrane space. While overexpression of anti-apoptotic Bcl-2 eliminates MAC activity, oligomers of the pro-apoptotic members Bax and/or Bak are essential structural component(s) of MAC. Assembly of MAC from Bax or Bak was monitored in real time by directly patch-clamping mitochondria with micropipettes containing the sentinel tBid, a direct activator of Bax and Bak. Herein, a variety of high affinity inhibitors of MAC (iMAC) that may prove to be crucial tools in mechanistic studies have recently been identified. This review focuses on characterization of MAC activity, its regulation by Bcl-2 family proteins, and a discussion of how MAC can be pharmacologically turned on or off depending on the pathology to be treated.
Open Access
Pharmacogenomics of Alzheimer's disease: genetic determinants of phenotypic variation and therapeutic outcome
(SciTech Central, 2016-11-16) Cacabelos, Ramón; Carril, Juan Carlos; Cacabelos, Pablo; Teijido Hermida, Óscar; Goldgaber, Dmitry; Ciencias de la Salud; Osasun Zientziak
Alzheimer's disease is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Conventional anti-dementia drugs are not cost-effective, and pharmacological breakthroughs have not been achieved for the past 10 years. Major determinants of therapeutic outcome in Alzheimer's disease (AD) include age- and sex-related factors, pathogenic phenotype, concomitant disorders, treatment modality and polypharmacy, and pharmacogenetics. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety. Pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes represent the major genetic determinants of response to treatment in AD. In pharmacogenetic studies, APOE-4 carriers are the worst responders and APOE-3 carriers are the best responders to conventional treatments. Patients harboring a large (L) number of poly T repeats in intrón 6 of the TOMM40 gene (L/L or S/L genotypes) in haplotypes associated with APOE-4 are the worst responders whereas patients with short (S) TOMM40 poly T variants (S/S genotype), and to a lesser extent S/VL and VL/VL carriers, in haplotypes with APOE-3 are the best responders to treatment. Only 25% of the Caucasian population are extensive metabolizers for trigenic haplotypes integrating CYP2D6- CYP2C19-CYP2C9 variants. Patients harboring CYP-related por (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG- AG-CC) exhibit the lowest cholesterol levels and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Epigenetic aberrations (DNA methylation, histone modifications, miRNA dysregulation) in genes configuring the pharmacoepigenetic cascade also influence the response/resistance to drugs. Consequently, novel strategies in drug development, either preventive or therapeutic, for AD should take into consideration these pharmacogenetic determinants for treatment optimization.
Open Access
Genetic polymorphisms of CYP2C19 in Ecuadorian population: an interethnic approach
(Elsevier, 2024) Alonso Llorente, Alba; Salgado Garrido, Josefa; Teijido Hermida, Óscar; González Andrade, Fabricio; Valiente Martín, Alberto; Fanlo Villacampa, Ana; Vicente Romero, Jorge; Ciencias de la Salud; Osasun Zientziak
Introduction: CYP2C19 is a highly polymorphic gene responsible for metabolizing commonly used drugs. CYP2C192,3 (loss of activity alleles) and 17 (increased activity allele) are the principal alleles included in clinical guidelines, however their prevalence varies among different ethnicities. Ecuadorian population is formed by Mestizos, Afrodescendants and Native Americans and frequency of CYP2C19 alleles could be different among them. The objective of this study was to establish the frequency of these variants in the different populations of Ecuador and to compare them with other populations. Materials and methods: DNA from 105 Afrodescendants, 75 Native Americans of the Kichwa ethnicity, and 33 Mestizos Ecuadorians was analyzed by nested-PCR to identify CYP2C1917 carriers. CYP2C192 allele was analyzed in DNA from 78 Afrodescendants, 29 Native Americans of the Kichwa, and 16 Mestizos by TaqMan Allelic Discrimination Assay. CYP2C193 was analyzed in 33 Afrodescendants by nested-PCR. Results: The global frequencies of the alternate alleles were 14.22% (CYP2C192) and 2.10% (CYP2C1917). No differences (p > 0.05) were observed among the subgroups. No CYP2C193 carrier was identified. CYP2C192 frequencies in Ecuador were similar to the ones reported in Europe, Africa and Middle East countries and to some American populations. Low CYP2C1917 frequencies, like the ones in our population, were also observed in East and South Asia and in Native American groups. Discussion: Absence of differences in the ethnic groups in Ecuador for CYP2C192 and 17 could be due to either a bias in sample selection (ethnic group was assed by self-identification) or to a high interethnic admixture in the Ecuadorian population that would had diluted genetic differences. In addition, CYP2C192, *3, and *17 alleles frequencies in our study suggest that Ecuadorians ancestry is mostly of Native American origin.
Open Access
Regulation of Bax mitochondrial localization by Bcl-2 and Bcl-xL: keep your friends close but your enemies closer
(Elsevier, 2013) Renault, Thibaud T.; Teijido Hermida, Óscar; Antonsson, Bruno; Dejean, Laurent M.; Manon, Stéphen; Ciencias de la Salud; Osasun Zientziak
Bax-induced mitochondrial outer membrane permeabilization (MOMP) is considered as one of the key control switches of apoptosis. MOMP requires Bax relocation to and insertion into the outer mitochondrial membrane to oligomerize and form pores allowing the release of apoptogenic factors such as cytochrome c. Even if these essential steps are now well-defined, it is necessary to better understand the molecular changes underlying the switch between inactive Bax and active (pore-forming) Bax. One of the ongoing issues is to determine whether Bax mitochondrial translocation is a critical step in the control of Bax activation or if this control is carried by latter regulatory steps. In this focus article we discuss recent data suggesting that although Bcl-2 and Bcl-xL block the MOMP, they can also regulate the mitochondrial Bax content. A new model in which Bax inhibition by Bcl-xL occurs at the immediate proximity of the outer mitochondrial membrane is also discussed. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.