Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1007/s00401-024-02780-4

Type

Journal article

Journal

Acta Neuropathol

Publication Date

21/09/2024

Volume

148

Keywords

ALS, Antisense oligonucleotides, Autophagy, Digital PCR, Post-translational modification, Animals, Autophagy-Related Proteins, Humans, DNA-Binding Proteins, Mice, Microtubule-Associated Proteins, Amyotrophic Lateral Sclerosis, Cysteine Endopeptidases, Male, Spinal Cord, Autophagy, Mice, Knockout, RNA Splicing, Female, Mice, Transgenic, Motor Neurons, Oligonucleotides, Antisense