Here we show that the Hsp70 isoform HspA5 specifically binds to the RNA-binding domain of TDP-43, that there is an apparent increased expression of cytoplasmic HspA5 in the prefrontal cortex of ALS patients and that upregulation of the HspA5 homologue mitigates TDP-43-induced toxicity in Drosophila, identifying HspA5 as a potential target in TDP-43-associated disease. This evidence concerns the gene HSPA1A and amyotrophic lateral sclerosis.