FIG 11.
Diagram showing possible mechanistic effect of the inhibitors of GSK3 on DM1 pathogenesis. According to the findings in the current study and previous work, the inhibitors of GSK3 normalize the levels of GSK3β and cyclin D3 and convert inactive CUGBP1REP into active CUGBP1ACT in DM1. The correction of this pathway occurs in skeletal muscle and in brain, and possibly in other tissues, affected in DM1, and the downstream targets of CUGBP1 in skeletal muscle and in brain might be corrected. In addition, TG reduces the mutant DMPK mRNA. The mechanisms of this effect remain to be determined. However, it is likely that correction of CUGBP1 is a part of these mechanisms. It is expected that the reduction of the mutant DMPK mRNA will reduce main toxic events downstream of the mutant CUG repeats and might include the feedback normalization of GSK3β.