Our results establish that either loss or gain of TDP-43 function in muscle and glial cells can lead to cytological and behavioural phenotypes in Drosophila that also characterize ALS and FTLD and thus demonstrate that in addition to neuronal pathology, glial- and muscle-specific TDP-43 dysfunction can directly contribute to disease formation. Here, TARDBP is linked to amyotrophic lateral sclerosis.