TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition

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dc.contributor.authorTorres, Pascual
dc.contributor.authorRico-Ríos, Santiago
dc.contributor.authorCeron-Codorniu, Miriam
dc.contributor.authorSantacreu-Vilaseca, Marta
dc.contributor.authorSeoane-Miraz, David
dc.contributor.authorJad, Yahya
dc.contributor.authorAyala, Victòria
dc.contributor.authorMariño, Guillermo
dc.contributor.authorBeltrán, Maria
dc.contributor.authorMiralles, Maria P.
dc.contributor.authorAndrés Benito, Pol
dc.contributor.authorFernández Irigoyen, Joaquín
dc.contributor.authorSantamaría Martínez, Enrique
dc.contributor.authorLópez-Otín, Carlos
dc.contributor.authorSoler, Rosa M.
dc.contributor.authorPovedano, Mónica
dc.contributor.authorFerrer, Isidro
dc.contributor.authorPamplona, Reinald
dc.contributor.authorWood, Matthew J. A.
dc.contributor.authorVarela, Miguel A.
dc.contributor.authorPortero-Otin, Manuel
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2025-03-05T18:14:19Z
dc.date.available2025-03-05T18:14:19Z
dc.date.issued2024-09-21
dc.date.updated2025-03-05T17:43:40Z
dc.description.abstractAmyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b−/− mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.en
dc.description.sponsorshipOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. G.M. was supported by grants from Ministerio Ciencia e Innovación (Spain) (PID2021-127534OB-I00). M.P.-O. and R.M.S. were supported by grants from Instituto de Salud Carlos III (PI20/000155, PI23/00176 and PI20/00098). R.P. was supported by Generalitat de Catalunya (2021 SGR 00990). P.T. was supported by an Unzué-Luzón grant. P.T. received a Margarita Salas postdoctoral fellowship from the Spanish Ministry of Universities (Spanish Government) which was supported by NextGenerationEU. Work supported by IRBLleida Scientific and Technical Service of Immunohistochemistry.
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dc.format.mimetypeapplication/zipen
dc.identifier.citationTorres, P., Rico-Ríos, S., Ceron-Codorniu, M., Santacreu-Vilaseca, M., Seoane-Miraz, D., Jad, Y., Ayala, V., Mariño, G., Beltrán, M., Miralles, M. P., Andrés-Benito, P., Fernandez-Irigoyen, J., Santamaria, E., López-Otín, C., Soler, R. M., Povedano, M., Ferrer, I., Pamplona, R., Wood, M. J. A., Varela, M. A., Portero-Otin, M. (2024) TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition. Acta Neuropathologica, 148(1), 1-22. https://doi.org/10.1007/s00401-024-02780-4.
dc.identifier.doi10.1007/s00401-024-02780-4
dc.identifier.issn0001-6322
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/53674
dc.language.isoeng
dc.publisherSpringer
dc.relation.ispartofActa Neuropathologica, (2024) 148:45
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-127534OB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII//PI20%2F000155/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII /Plan Estatal de Investigación Científica, Técnica y de Innovación para el periodo\n2021-2023/PI23%2F00176/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI20%2F00098/ES/
dc.relation.publisherversionhttps://doi.org/10.1007/s00401-024-02780-4
dc.rights© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectALSen
dc.subjectAntisense oligonucleotidesen
dc.subjectAutophagyen
dc.subjectDigital PCRen
dc.subjectPost-translational modificationen
dc.titleTDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibitionen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication86d1b76e-4790-40b1-a3ec-72331c5c6199
relation.isAuthorOfPublicationabacfd17-2b93-4d99-bae2-52053d57401e
relation.isAuthorOfPublication.latestForDiscovery86d1b76e-4790-40b1-a3ec-72331c5c6199

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