An age-related reduction of brain TBPH/TDP-43 levels precedes the onset of locomotion defects in a Drosophila ALS model.

•TDP-43 levels decrease physiologically during aging in Drosophila and mice.•The reduction is seen at protein and mRNA level in the brain.•Aggregation does not hamper normal development and early adult life.•TBPH reduction combined with the presence of aggregates triggers a locomotive defect.•A similar pathway may be active in the pathogenesis of human ALS.