Osmolytes dynamically regulate mutant Huntingtin aggregation and CREB function in Huntington's disease cell models.

Osmolytes are organic solutes that change the protein folding landscape shifting the equilibrium towards the folded state. Herein, we use osmolytes to probe the structuring and aggregation of the intrinsically disordered mutant Huntingtin (mHtt) vis-a-vis the pathogenicity of mHtt on transcription factor function and cell survival. Using an inducible PC12 cell model of Huntington's disease (HD), we show that stabilizing polyol osmolytes drive the aggregation of Htt103Q-EGFP from a diffuse ensemble into inclusion bodies (IBs), whereas the destabilizing osmolyte urea does not.