TDP-43 is an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) 
that is known to regulate the splicing, transport, and storage of specific mRNAs 
into stress granules. Although TDP-43 has been shown to interact with 
translation factors, its role in protein synthesis remains unclear, and no in 
vivo translation targets have been reported to date. Here we provide evidence 
that TDP-43 associates with futsch mRNA in a complex and regulates its 
expression at the neuromuscular junction (NMJ) in Drosophila. In the context of 
TDP-43-induced proteinopathy, there is a significant reduction of futsch mRNA at 
the NMJ compared with motor neuron cell bodies where we find higher levels of 
transcript compared with controls. TDP-43 also leads to a significant reduction 
in Futsch protein expression at the NMJ. Polysome fractionations coupled with 
quantitative PCR experiments indicate that TDP-43 leads to a futsch mRNA shift 
from actively translating polysomes to nontranslating ribonuclear protein 
particles, suggesting that in addition to its effect on localization, TDP-43 
also regulates the translation of futsch mRNA. We also show that futsch 
overexpression is neuroprotective by extending life span, reducing TDP-43 
aggregation, and suppressing ALS-like locomotor dysfunction as well as NMJ 
abnormalities linked to microtubule and synaptic stabilization. Furthermore, the 
localization of MAP1B, the mammalian homolog of Futsch, is altered in ALS spinal 
cords in a manner similar to our observations in Drosophila motor neurons. 
Together, our results suggest a microtubule-dependent mechanism in motor neuron 
disease caused by TDP-43-dependent alterations in futsch mRNA localization and 
translation in vivo.