**2.10 ALS10 (TARDBP)**

TDP-43 was identified as one of the main components of ubiquitinated cytoplasmic inclusions in ALS and FTD (Neumann et al., 2006). Sequencing of the gene encoding this protein (*TARDBP*) identified mutations in ALS patients (Kabashi et al., 2008; Shreedharan et al., 2008). To date over 40 mutations in *TARDBP* have been identified in several different populations with a frequency of ~5% of fALS cases and up to 2% of sALS cases (Corrado et al., 2009; Iida et al., 2010; Millecamps et al., 2010; Ticozzi et al., 2009; Van Deerlin et al., 2008). *TARDBP* mutations have also been observed in ALS-FTD and FTD patients (Benajiba et al., 2009; Gitcho et al., 2009b). Despite the presence of *TARDBP* mutations in only a portion of ALS and FTD patients, TDP-43-positive cytoplasmic inclusions are found in almost all ALS patients but they are also seen in other neurodegenerative diseases such as FTD, Huntington's, Alzheimer's, and Parkinson's disease (Da Cruz and Cleveland, 2011).

TDP-43, like FUS, is a DNA/RNA binding protein that is part of the heterogeneous ribonucleoprotein family. It has a role in gene transcription, regulation of splicing, and mRNA transport and stabilization (Buratti and Baralle, 2010). Except for one truncation mutation, all *TARDBP* mutations identified in ALS patients are missense mutations clustered in the glycine-rich C-terminal region which is involved in protein-protein interactions (Lagier-Tourenne et al., 2010). *TARDBP* mutations lead to an abnormal distribution of the protein to the cytoplasm.
