Fig. 7

Schematic representation of Notch1-mediated regulation of Akt signaling disturbed by TDP-∆C protein. Notch1 is transcriptionally regulated by TDP-43 protein (Fig. 5). Under physiological conditions, Notch1 indirectly suppresses Pten expression, a negative regulator of Akt signaling, through transcriptional regulation of Hes1 (upper panel). Under pathological conditions, however, the cleaved TDP-43 N-terminal fragment (TDP-∆C) reduces Notch1 expression. Decreased Notch1 results in increased Pten expression leading to the inactivation of Akt (lower panel). Inactivation of Akt may disturb normal synaptic function of motor neurons and cause motor dysfunction