Fibrillogenic and Non-fibrillogenic Ensembles of SDS-bound Human Alpha-synuclein

Fibril formation of alpha-synuclein is associated with several neurodegenerative diseases, including Parkinson's disease in humans. The anionic detergent sodium dodecyl sulfate (SDS) can accelerate the fibril formation in vitro. However, the molecular basis of this acceleration is not clear. Our study shows that native alpha-synuclein exhibits relatively less fibril growth despite providing fibril seeds for nucleation. The presence of SDS promotes the seeded fibril growth in a concentration-dependent manner, with an optimal concentration of 0.5-0.75 mM. We used isothermal calorimetry, hydrophobic dye binding and circular dichroism spectroscopy to characterize the protein-detergent interactions as a function of the concentration of SDS. Interaction of SDS with alpha-synuclein when studied by isothermal titration calorimetry and hydrophobic dye-binding reveals a similar characteristic optimal behavior between 0.5 mM and 0.75 mM SDS. The study shows two types of ensembles of alpha-synuclein and SDS: the fibrillogenic ensembles formed with optimal concentration of SDS around 0.5-0.75 mM are characterized by enhanced accessible hydrophobic surfaces and extended to partially helical conformation, while the less or non-fibrillogenic ensembles formed above 2 mM SDS are characterized by less accessible hydrophobic surfaces and maximal helical content. Little or no fibrillogenicity of the ensembles observed above 2 mM SDS could be partly because of the observed intrinsic instability of the fibrils under the condition.