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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 <jats:italic>ATG4B<\/jats:italic>, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A\/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), <jats:italic>Atg4b<\/jats:italic> 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 <jats:italic>atg4b<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore <jats:italic>ATG4B<\/jats:italic> mRNA in <jats:italic>TARDBP<\/jats:italic> knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. 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