While the role of abnormal TDP-43 accumulation in both primary and secondary TDP-43 proteinopathies is not yet fully understood, the identification of TDP-43 mutations associated with ALS and FTD (~40 at present) has provided clear evidence that altered TDP-43 processing can be a primary cause of neurodegeneration and is not just a secondary phenomenon [9,10]. This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.