S6K1 Inhibition-Mediated Changes in Motoneuron Properties in a Mouse Model of Amyotrophic Lateral SclerosisPublic Deposited
Amyotrophic lateral sclerosis (ALS) is characterized by progressive motoneuron loss. Autopsy from thoracic spinal tissues of sALS patients revealed a significant loss of large motoneurons while medium and small motoneurons were relatively unaffected. Using two-photon microscopy, we observed a soma hypertrophy of neonatal motoneurons in mice overexpressing mutant human G93A-superoxide dismutase1 (hG93A-SOD1). Input conductance and persistent inward current (PIC) were also upregulated in neonatal hG93A-SOD1 mice, whereas excitability was maintained, likely due to the opposite effects of input conductance and PIC. Inhibition of p70 ribosomal protein S6 kinase (S6K1) activities by PF-4708671 successfully restored motoneuron size, input conductance and PIC. However, the effect of PF-4708671 was much larger in hG93A-SOD1 than wild-type motoneurons, suggesting that S6K1/ribosomal protein S6 (rpS6) management was hypersensitive in the mutants and that the reductions in cell size, input conductance and PIC were excessive. Consistent with this, the inhibition of S6K1 induced a significant subpopulation of hypoexcitable hG93A-SOD1 motoneurons, suggesting that this inhibition impaired the function of some motoneurons. Adult hG93A-SOD1 mice treated with PF-4708671 showed accelerated disease onset and progression likely due to observed hyperexcitability and affected protein translation control. We concluded that inhibiting S6K1 alone was enough in augmenting ALS which emphasized the importance of S6K1/rpS6 management and protein translation control in ALS.