Modulation of conformational integrity and aggregation propensity of α-synuclein by osmolytes: Implications in therapeutic intervention of Parkinson's disease.

Abstract

Understanding the factors capable of modulation of conformational stability and aggregation propensity of α-synuclein (α-Syn), a hallmark of Parkinson's disease (PD), is crucial for developing future therapeutic interventions for this disease. This chapter aims at exploring the roles of osmolytes in affecting the structural dynamics of α-Syn as well as focuses on how these osmolytes impact folding, stability, and aggregation behavior of this important intrinsically disordered protein. A number of potent osmolytes, including trimethylamine N-oxide (TMAO), trehalose, myo-inositol, taurine, glycine, glutamate, and glycerol were discussed along with their overall effect on α-Syn. These osmolytes can stabilize native conformations or promote alternative folding pathways, thereby influencing α-Syn aggregation. The chapter highlights the dual role of osmolytes in either preventing or exacerbating aggregation, depending on their concentration and interaction mechanism with α-Syn. Moreover, by integrating current research results, the chapter provides insights into how osmolytes might be utilized for therapeutic interventions with potential avenues for managing PD. Overall, the chapter underscores the significance of osmolyte-induced modulation of α-Syn aggregation in the context of PD and highlights future research areas in this direction.