Sonic Hedgehog and TDP-43 participate in 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. Transactive response DNA-binding protein of 43 kDa (TDP-43) is a nuclear DNA/RNA binding protein involved in transcription and RNA processing. Recent findings have reported cytoplasmic inclusions containing TDP-43 in amyotrophic lateral sclerosis. Although substantial attention has been given to the toxic effects of this protein, the functional role of TDP-43 remains largely unclear. 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 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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (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 parts of a complex mechanism of neuroplasticity in a mouse model of SC motoneuron disease.