ROCK inhibition improves axonal regeneration in a preclinical model of amyotrophic lateral sclerosis

: Alteration of the RhoA/ROCK (Rho kinase) pathway has been shown to be neuroprotective in SOD1G93A mice, the most commonly used animal model of ALS. Since previous studies indicate that, apart from neuroprotection, ROCK inhibitor Y-27632 can also accelerate regeneration of motor axons, we here assessed the regenerative capability of axons in SOD1G93A mice with and without treatment with Y-27632. Regeneration of axons was examined after sciatic nerve crush in pre- and symptomatic SOD1G93A mice. Proregenerative effects of Y-27632 were studied during the disease course in the SOD1G93A mouse model. In symptomatic SOD1G93A mice, axonal regeneration was markedly reduced compared to presymptomatic SOD1G93A mice and wild types. Treatment with Y-27632 improved functional and morphological measures of motor axons after sciatic crush in all tested conditions. Y-27632 treatment did not increase the lifespan of symptomatic SOD1G93A mice, but did improve axonal (re)innervation of neuromuscular junctions. Our study provides proof of concept that axonal regeneration of motor neurons harboring SOD1G93A is impaired, but amenable for pharmacological interventions aiming to accelerate axonal regeneration. Given the lack of treatments for ALS, approaches to improve axonal regeneration, including by inhibiting ROCK, should be further explored.