Fig. 5

A schematic model of abnormal elevation of the MEK/ERK pathway and immune overactivation in TDP-43-induced cytotoxicity. In this study, we uncover that dERK (rl) and the MEK/ERK pathway is abnormally upregulated in TDP-43 flies, which induces immune overactivation. Neuron-specific downregulation of the MEK/ERK signaling or the immune AMPs such as AttC and DptB significantly suppresses TDP-43 toxicity. Moreover, the MEKi trametinib ameliorates TDP-43-induced degenerative phenotypes and extends the lifespan in flies. Together, MEKi may be a potential target for developing new therapeutic strategies to treat ALS and related diseases