Overexpression of , , improves motor neuron degeneration induced by knockdown of , .

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the motor neuron degeneration that eventually leads to complete paralysis and death within 2-5 years after disease onset. One of the major pathological hallmark of ALS is abnormal accumulation of inclusions containing TAR DNA-binding protein-43 (TDP-43). TDP-43 is normally found in the nucleus, but in ALS, it localizes in the cytoplasm as inclusions as well as in the nucleus. Loss of nuclear TDP-43 functions likely contributes to neurodegeneration. is the ortholog of human . In the present study, we confirmed that models harboring knockdown develop locomotive deficits and degeneration of motoneurons (MNs) due to loss of its nuclear functions, recapitulating the human ALS phenotypes. We previously suggested that , the ortholog of human (), is a modulator of degeneration in MNs induced by knockdown of , the ortholog of human . In this study, to determine the effects of VCP on TDP-43-assosiated ALS pathogenic processes, we examined genetic interactions between and . Overexpression of suppressed the compound eye degeneration caused by knockdown and suppressed the morbid phenotypes caused by neuron-specific knockdown, such as locomotive dysfunction and degeneration of MN terminals. Further immunocytochemical analyses revealed that the suppression is caused by restoring the cytoplasmically mislocalized TBPH back to the nucleus. In consistent with these observations, a loss-of-function mutation of enhanced the compound eye degeneration caused by knockdown, and partially enhanced the locomotive dysfunction caused by knockdown. Our data demonstrated that expression levels of influenced the phenotypes caused by knockdown, and indicate that reagents that up-regulate the function of human VCP could modify MN degeneration in ALS caused by TDP-43 mislocalization.