Degenerative nervous system disorders are characterized by a massive build up of "misfolded" (crumpled) proteins (molecules) that deposit in the brain and spinal cord. These disease proteins differ in specific disorders but they form distinct brain/spinal cord pathologies that are diagnostic of specific neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Evidence shows that FTLD and ALS represent related disorders with different clinical manifestations that are linked to ubiquitin tagged inclusions or deposits (UBIs). Indeed, 20% of FTLD patients have ALS and 10% of ALS patients have FTLD. UBIs predominate in neurons of ALS and FTLD patients with UBI pathology (termed FTLD-U). Hence, our discovery that TDP-43 is the ubiquitin tagged disease protein in UBIs of ALS and FTLD-U as well as more recent discoveries of >25 mutations in the TDP-43 gene (TARDBP) that are pathogenic for inherited ALS in rare families support our view that ALS and FTLD-U represent different clinical presentations of a single disease, i.e. TDP-43 proteinopathy. For these reasons, this proposal will establish mouse models of TDP-43 proteinopathy to: 1) determine if TDP-43 pathology of FTLD-U/ALS are recapitulated in these models; 2) elucidate the role of TDP-43 in causing FTLD-U/ALS. This will set the stage for identifying disease modifying therapies for patients with FTLD-U/ALS.