However, it is well recognized that the aggregation of hyper-phosphorylated and ubiquitinated TDP-43 protein into cytoplasmic inclusions represents one of the primary neuropathological hallmarks of ALS, supporting the contribution of TDP-43 pathology to neurodegeneration.3,4 In a physiological state, TDP-43 is mainly localized in the nucleus, where it controls gene expression and pre-mRNA splicing, and modulates the regulation of its own mRNA, as discussed above. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.