Overall, TDP-43 dysfunction due to various factors, such as imbalance of nucleo-cytoplasmic distribution, dysregulations of RNA metabolism, genetic mutations, aberrant post-translational modifications, aggregation, and gain of cytotoxicity, induces the collapse of cellular homeostasis and leads to TDP-43 proteinopathy in ALS and FTLD-TDP. This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.