To investigate the molecular mechanisms involved in the onset and progression of TDP-43 proteinopathy, we developed an in vitro model of highly homogeneous murine upper motor neurons (UMNs), i.e., glutamatergic neurons of layers V and VI, amenable to lentiviral transduction with human TDP-43, wild-type (wt) or carrying an ALS-mutation (Gitcho et al., 2008). Here, TARDBP is linked to amyotrophic lateral sclerosis.