Carregant...
Fitxers
Tipus de document
ArticleVersió
Versió publicadaData de publicació
Llicència de publicació
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/216650
TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition
Títol de la revista
Director/Tutor
ISSN de la revista
Títol del volum
Recurs relacionat
Resum
Amyotrophic 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.
Matèries (anglès)
Citació
Citació
TORRES, Pascual, RICO-RIOS, Santiago, CERON-CODORNIU, Miriam, SANTACREU-VILASECA, Marta, SEOANE-MIRAZ, David, JAD, Yahya, AYALA, Victòria, MARIÑO, Guillermo, BELTRAN PERELLÓ, Maria, MIRALLES, Maria p., ANDRÉS-BENITO, Pol, FERNÁNDEZ IRIGOYEN, Joaquín, SANTAMARÍA, Enrique, LÓPEZ-OTIN, Carlos, SOLER, Rosa m., POVEDANO, Mònica, FERRER, Isidro (ferrer abizanda), PAMPLONA, Reinald, WOOD, Matthew j.a., VARELA, Miguel a., PORTERO-OTIN, Manuel. TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition. _Acta Neuropathologica_. 2024. Vol. 148, núm. 1. [consulta: 20 de gener de 2026]. ISSN: 0001-6322. [Disponible a: https://hdl.handle.net/2445/216650]