Sonic hedgehog and TDP-43 participate to the spontaneous locomotor recovery in a mouse model of spinal motoneuron disease

Several studies have attempted to repair the damaged spinal cord (SC) by stimulating neurogenesis or neuroplasticity, with limited success. Sonic hedgehog (Shh) is involved in neural induction and stem cell functioning, but recent findings also suggest its role in regeneration and functional recovery. TDP-43 is a nuclear protein involved in mRNA processing. Recently, TDP-43 has been found in the cytoplasmic inclusions observed in amyotrophic lateral sclerosis. Substantial attention has been devoted to the toxic effects of TDP-43, whereas the functional role of this protein remains poorly investigated. We used a mouse model of neurotoxic motoneuron depletion to study the role of the above-described factors in the compensatory changes occurring after the lesion. The injection of cholera toxin-B saporin into the gastrocnemius muscle caused a partial motoneuron death accompanied by a glial reaction and an impairment of locomotion. Interestingly, motor activity was significantly restored as soon as one month later. Moreover, we observed an activity-dependent modification of Shh and synaptic proteins (synapsin-I and AMPA receptors). Notably, the motor performance of lesioned animals correlated with the expression of synapsin-I and Shh. Conversely, the expression of Shh significantly correlated with the levels of synapsin-I, GluR2 and TDP-43. The results suggest that Shh and TDP-43 are crucial part of a complex mechanism of neuroplasticity in a mouse model of SC motoneuron disease.