Using two different cell models (HEK293T and human neuroblastoma SH-SY5Y cell lines), we found that USP19 overexpression significantly enhances the secretion of TDP-43 mutants (the familial ALS TDP-43-K263E variant and the truncated TDP-43–ΔNLSΔ187-192- mutant) as free aggregates or soluble misfolded TDP-43. Here, USP19 is linked to amyotrophic lateral sclerosis.