Accordingly, several studies report that loss of TDP-43, as well as the presence of ALS-associated TDP-43 mutations, induce DNA damage in cell lines, neuronal cultures, transgenic mouse models, and ALS patient tissues [371–376] – and the resulting genome instability has been proposed as an additional driver of neurodegeneration in TDP-43 proteinopathies. This evidence concerns the gene TARDBP and proteostasis deficiencies.