Inhibition of leucine‐rich kinase 2 (LRRK2) promotes peripheral axon regeneration via phosphorylation‐network remodelling

Background and Purpose In contrast to neurons in the central nervous system, neurons in the peripheral nervous system can regenerate axons after injury via activation of a pro‐regenerative transcriptional programme. Pathogenic mutations in leucine‐rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, and several small‐molecule LRRK2 kinase inhibitors have been developed, with some in clinical trials. However, the physiological role of endogenous, non‐pathogenic LRRK2 remains largely unknown. Experimental Approach LRRK2 expression was examined in murine dorsal root ganglia (DRGs) following sciatic nerve crush (SNC) injury. Regenerative axon growth was assessed using cultured adult DRG neurons after genetic or pharmacological inhibition of LRRK2. Axon regeneration after SNC injury was evaluated in vivo following oral administration of the LRRK2 inhibitors, MLi‐2 or PF‐06447475. Axonal trafficking experiments and phosphoproteomic analyses were performed to investigate mechanisms underlying axon growth promotion induced by LRRK2 inhibitors. Key Results SNC injury reduced LRRK2 expression in DRGs. Genetic and pharmacological inhibition of LRRK2 enhanced regenerative axon growth in culture. Oral administration of MLi‐2 or PF‐06447475 promoted axon regeneration in vivo after SNC injury. MLi‐2 enhanced mitochondrial trafficking, and phosphoproteomic analyses identified cellular processes and kinase‐substrate signalling networks associated with a pro‐regenerative state triggered by LRRK2 inhibition. Conclusion and Implications These findings identify endogenous, non‐pathogenic LRRK2 as a suppressor of axon regeneration. They also support the potential repositioning of small‐molecule LRRK2 inhibitors, including clinically advanced compounds and those in preclinical development, as therapeutic strategies to enhance peripheral nerve regeneration.