Examinando por Autor "Gil Bea, Francisco Javier"

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    Computational analysis of ELOVL6 structure and inhibition for rational drug design
    (American Chemical Society, 2026-06-05) Ibarluzea, Markel G.; Ramis Cortés, Rafael; Fuentetaja, Martín; Gil Bea, Francisco Javier; Gereñu Lopetegi, Gorka; López de Munain Arregui, Adolfo ; Aizpurua Iparraguirre, Jesus Mari ; Miranda, Jose I.; Bergara, Aitor; Leonardo, Aritz
    ELOVL6 is a key enzyme in long-chain fatty acid elongation, catalyzing the conversion of C16 fatty acids into C18 fatty acids. While its role in lipid metabolism is well established, recent studies have linked ELOVL6 to metabolic and neurodegenerative diseases, making it an attractive therapeutic target. However, the absence of a resolved crystal structure and limited mechanistic understanding of its inhibition pose significant challenges for drug discovery. In this study, we employ a multitiered computational approach, including structure prediction, molecular dynamics (MD) simulations, and free energy calculations, to investigate the structural basis of ELOVL6 function and inhibition. We identify the most thermodynamically favorable substrate binding pathway and characterize key conformational changes associated with ligand binding. By analyzing potential inhibitor binding pockets, we determine that known inhibitors preferentially target the active site, and we validate their binding affinities against experimental data. Additionally, by comparing ELOVL6 with homologous elongases, we pinpoint potentially key amino acid residues responsible for selectivity, providing insights that could guide structure-based drug design. Our findings establish a mechanistic framework for rational inhibitor development, offering a foundation for future efforts in optimizing ELOVL6-targeting therapeutics.
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    Ítem
    Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis
    (Springer Science and Business Media Deutschland GmbH, 2024-09-16) Zufiría García, Mónica; Pikatza-Menoio, Oihane; Garciandia Arcelus, Maddi; Bengoetxea Bausela, Xabier; Jiménez Zúñiga, Andrés; Elicegui, Amaia; Levchuk, María; Arnold García, Olatz; Ondaro Ezkurra, Jon; Iruzubieta Agudo, Pablo; Rodríguez Gómez, Laura; Fernández Pelayo, Uxoa; Muñoz Oreja, Mikel; Aiastui Pujana, Ana; García Verdugo, Jose Manuel; Herranz Pérez, Vicente; Zulaica, Miren; Poza Aldea, Juan José; Ruiz Onandi, Rebeca; Fernández Torrón, Roberto; Espinal Valencia, Juan Bautista; Bonilla Zagala, Mario; Lersundi Artamendi, Ana; Fernández-Eulate, Gorka; Riancho Zarrabeitia, Javier; Vallejo Illarramendi, Ainara; Holt, Ian James; Sáenz, Amets; Malfatti, Edoardo; Duguez, Stéphanie; Blázquez García, Lorea; López de Munain Arregui, Adolfo; Gereñu Lopetegi, Gorka; Gil Bea, Francisco Javier; Alonso-Martin, Sonia
    Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.