Examinando por Autor "Pikatza-Menoio, Oihane"

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    Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features
    (Oxford University Press, 2024-08) Iruzubieta Agudo, Pablo; Damborenea Moreno, Alberto; Ioghen, Mihaela; Bajew, Simon; Fernández Torrón, Roberto; Töpf, Ana; Herrero Reiriz, Álvaro; Epure, Diana; Vill, Katharina; Hernández Laín, A.; Manterola Larrañaga, María; Azkargorta, Mikel; Pikatza-Menoio, Oihane; Pérez-Fernandez, Laura; García Puga, Mikel; Gaina, Gisela; Bastian, Alexandra; Streata, Ioana; Walter, Maggie C.; Müller-Felber, Wolfgang; Thiele, Simone; Moragón Rodríguez, Saioa; Bastida Lertxundi, Nerea; López Cortajarena, Aitziber; Elortza, Felix; Gereñu Lopetegi, Gorka; Alonso-Martin, Sonia; Straub, Volker; Sacho, David de; Teleanu, Raluca; López de Munain Arregui, Adolfo; Blázquez García, Lorea
    Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies, where mutations in genes involved in RNA metabolism or characterized by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle MRI, with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterized by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although inter-individual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganization. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients’ muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.
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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.