Activation of Elk-1 participates as a neuroprotective compensatory mechanism in models of Huntington's disease

The transcription factor Elk-1 has been revealed as neuroprotective against toxic stimuli. In this study, we explored the neuroprotective capacity of Elk-1 in Huntingtons disease. To this aim, we used two exon-1 mutant huntingtin (mhtt) mouse models (R6/1 and R6/2), and a full-length mhtt striatal cell model (STHdhQ111/Q111). Analysis of Elk-1 and pElk-1Ser383 in the striatum of R6 mice revealed increased levels during the disease progression. Similarly, Elk-1 and pElk-1Ser383 levels were increased in STHdhQ111/Q111 cells when compared with wild-type cells. In addition, we observed a predominant nuclear localization of Elk-1 in STHdhQ111/Q111 cells, and in the striatum of 30-week-old R6/1 mice. Nuclear Elk-1 did not colocalize with mhtt aggregates, suggesting a higher transcriptional activity. In agreement, the knock-down of Elk-1 decreased immediate early genes expression in STHdhQ111/Q111 cells, but not in wild-type cells. Interestingly, reduction of Elk-1 levels by siRNAs transfection promoted cell death and caspase 3 cleavage in STHdhQ111/Q111 cells, but not in wild-type cells. In summary, we propose that increased protein levels, phosphorylation and nuclear localization of Elk-1 observed in exon-1 and full-length Huntingtons disease models could be a compensatory mechanism activated by striatal cells in response to the presence of mhtt that contributes to neuroprotection.