The discovery of the nuclear factor TDP-43 involvement in neurodegenerative disease has increased significantly the general interest on the characteristics of this protein. The aberrant localization and aggregation of TDP-43 in affected tissues coupled with the tight auto regulation of TDP 43 cellular levels has suggested novel pathways for neurodegeneration. TDP 43 is predominantly a nuclear protein that shuttles between nucleus and cytoplasm. In disease neurons TDP 43 mislocalize to cytoplasmic inclusions with devastating consequences on neuronal survival. These cytoplasmic aggregation disrupts the TDP-43 control of its own cellular level. In fact autoregulation is mediated byan unusual splicing event in the 3’UTR of its pre mRNA for which is essentiial the presence of TDP 43 in the nucleus. In addition animal models and highthroughput assays have recently highlighted the role played by this protein in the regulation of hundreds of nuclear and cytoplasmic RNA transcripts, many of them belonging to key genes for neuronal metabolism. A model has been developed to study the determinants of the aggregation process and the impact of the latter on neuronal function. Animal models of the disease have been developed in different species mainly mice and flies.