In summary, our results suggest that osmolytes can reverse CREB dysfunction in our HD cell model by two apparently distinct mechanisms: (1) by promoting the structuring of mHtt into forming IBs effectively reducing the interactive surface area and negating the sequestration of CREB by diffuse mHtt as demonstrated with the stabilizing osmolytes, and (2) by disrupting the binding and sequestration of CREB by diffuse mHtt and perhaps other yet-to-be identified cellular proteins as shown by the effect of urea in de-repressing CREB activity without driving diffuse mHtt into forming IB. The gene discussed is CREB1; the disease is Huntington disease.