TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition
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<sup>-/-</sup> 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.
Authors
- Miguel A. Varela (ORCID: https://orcid.org/0000-0003-4376-9381)
- Isidró Ferrer (ORCID: https://orcid.org/0000-0001-9888-8754)
- María Beltran (ORCID: https://orcid.org/0000-0001-7965-2201)
- Maria P. Miralles (ORCID: https://orcid.org/0000-0003-3122-2143)
- Victòria Ayala
- Manuel Portero-Otı́n (ORCID: https://orcid.org/0000-0002-1823-0299)
- Pol Andrés‐Benito (ORCID: https://orcid.org/0000-0003-3000-0338)
- Pascual Torres (ORCID: https://orcid.org/0000-0001-7903-3478)
- David Seoane-Miraz
- Mónica Povedano (ORCID: https://orcid.org/0000-0001-5146-6183)
- Reinald Pamplona (ORCID: https://orcid.org/0000-0003-4337-6107)
- Yahya E. Jad (ORCID: https://orcid.org/0000-0002-6307-0482)
- Enrique Santamaría (ORCID: https://orcid.org/0000-0001-8046-8102)
- Joaquín Fernández‐Irigoyen (ORCID: https://orcid.org/0000-0001-5072-4099)
- Rosa M. Soler (ORCID: https://orcid.org/0000-0003-0528-3102)
- Guillermo Mariño (ORCID: https://orcid.org/0000-0003-1960-1677)
- Carlos López-Otı́n (ORCID: https://orcid.org/0000-0001-6964-1904)
- Matthew J. A. Wood (ORCID: https://orcid.org/0000-0002-5436-6011)
- Miriam Ceron-Codorniu
- Santiago Rico-Rios (ORCID: https://orcid.org/0000-0003-4219-423X)
- Marta Santacreu-Vilaseca
Institutions
- Universidad de Oviedo (ES)
- Bellvitge University Hospital (ES)
- University of Oxford (GB)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Navarrabiomed (ES)
- Instituto de Investigación Biomédica de Lleida (ES)
- Jenner Institute (GB)
- Instituto de Investigación Sanitaria del Principado de Asturias (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Acta Neuropathologica
- Published
- 2024-09-21
- DOI
- https://doi.org/10.1007/s00401-024-02780-4
- Citations
- 9
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 3.32
Funders
- Generalitat de Catalunya
- Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya
- Universitat de Lleida
- Medical Research Council
- Instituto de Salud Carlos III