Abstract: The present invention relates to Engrailed protein, a nucleic acid encoding Engrailed protein and compositions comprising the same for use in treating or preventing diseases associated with accumulation of TDP-43 in the cell, particularly in the cell cytoplasm. Also provided herein are in vitro methods of selecting a subject for such therapy by detecting cellular accumulation of TDP-43, particularly cellular cytoplasmic accumulation, in a biological sample of the subject. Also provided herein are in vitro methods of following a subject treated with such therapy by measuring cellular accumulation, particularly cellular cytoplasmic accumulation, of TDP-43 in a biological sample of the treated subject.