Bimodal regulation of axonal transport by the GDNF-RET signalling axis in healthy and diseased motor neurons

Deficits in axonal transport are one of the earliest pathological outcomes in several models of amyotrophic lateral sclerosis (ALS), including SOD1(G93A) mice. Evidence suggests that rescuing these deficits prevents disease progression, stops denervation, and extends survival. Kinase inhibitors have been previously identified as transport enhancers, and are being investigated as potential therapies for ALS. For example, inhibitors of p38 mitogen-activated protein kinase and insulin growth factor receptor 1 have been shown to rescue axonal transport deficits in vivo in symptomatic SOD1(G93A) mice. In this work, we investigated the impact of RET, the tyrosine kinase receptor for glial cell line-derived neurotrophic factor (GDNF), as a modifier of axonal transport. We identified the fundamental interplay between RET signalling and axonal transport in both wild-type and SOD1(G93A) motor neurons in vitro. We demonstrated that blockade of RET signalling using pharmacological inhibitors and genetic knockdown enhances signalling endosome transport in wild-type motor neurons and uncovered a divergence in the response of primary motor neurons to GDNF compared with cell lines. Finally, we showed that inhibition of the GDNF-RET signalling axis rescues in vivo transport deficits in early symptomatic SOD1(G93A) mice, promoting RET as a potential therapeutic target in the treatment of ALS.

Automated summary

This study investigates the interplay between the tyrosine kinase receptor RET for glial cell line-derived neurotrophic factor (GDNF) and axonal transport in neurons. By blocking RET signaling using inhibitors and genetic knockdown, the study demonstrates enhanced signaling endosome transport and rescue of axonal transport deficits in both wild-type and SOD1(G93A) motor neurons. These findings suggest RET as a potential therapeutic target for ALS treatment.