As recognized by previous studies, ALS-associated TDP-43 mutations possess higher stability and show increased half-life compared to the wild-type form.194,195 Moreover, disease-linked mutants are more rapidly turned over through the ubiquitin/proteasome system (UPS) system than wild-type TDP-43,196 making it likely that such modifications are the driving factors that alter the processing and translation of the TDP-43’s mRNAs and facilitate its mislocalization and precipitation. Here, TARDBP is linked to amyotrophic lateral sclerosis.