Promoting regeneration while blocking cell death preserves motor neuron function in a model of ALS

Wlaschin et al. show, in a mouse model of ALS, that combining DLK deletion to delay neuronal death with ATF3 expression to promote regeneration helps preserve motor neuron function. This serves as proof of concept for potential combinatorial treatments for ALS and other motor diseases. Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of motor neurons with very few treatment options. We had previously found that motor neuron degeneration in a mouse model of ALS can be delayed by deleting the axon damage sensor MAP3K12 or dual leucine zipper kinase (DLK). However, DLK is also involved in axon regeneration, prompting us to ask whether combining DLK deletion with a way to promote axon regeneration would result in greater motor neuron protection. To achieve this, we used a mouse line that constitutively expresses ATF3, a master regulator of regeneration in neurons. Although there is precedence for each individual strategy in the SOD1(G93A) mouse model of ALS, these have not previously been combined. By several lines of evidence including motor neuron electrophysiology, histology and behaviour, we observed a powerful synergy when combining DLK deletion with ATF3 expression. The combinatorial strategy resulted in significant protection of motor neurons with fewer undergoing cell death, reduced axon degeneration and preservation of motor function and connectivity to muscle. This study provides a demonstration of the power of combinatorial therapy to treat neurodegenerative disease.

Automated summary

Wlaschin et al. demonstrate that combining DLK deletion to delay neuronal death with ATF3 expression to promote regeneration effectively preserves motor neuron function in a mouse model of ALS. This study provides evidence for potential combinatorial therapies for ALS and other motor diseases.