Parkinson’s disease is a debilitating neurodegenerative disease with high morbidity in the aged population. This disease causes movement disorder, anxiety and dementia, bringing tremendous financial and societal burden on the patients and their family. α-Synuclein is a presynaptic protein that is a major component of the Lewy bodies and Lewy neurites, the pathophysiological hallmark of Parkinson’s disease. The physiological function of α-synuclein is not clear but its association with membrane is believed to play an important role for its function. In the presence of negatively charged membrane, α-synuclein undergoes a structural transition from unfolded state to significant α-helical conformation. Polyunsaturated fatty acids such as arachidonic acid and docosahexaenoic acid al...[ Read more ]

Parkinson’s disease is a debilitating neurodegenerative disease with high morbidity in the aged population. This disease causes movement disorder, anxiety and dementia, bringing tremendous financial and societal burden on the patients and their family. α-Synuclein is a presynaptic protein that is a major component of the Lewy bodies and Lewy neurites, the pathophysiological hallmark of Parkinson’s disease. The physiological function of α-synuclein is not clear but its association with membrane is believed to play an important role for its function. In the presence of negatively charged membrane, α-synuclein undergoes a structural transition from unfolded state to significant α-helical conformation. Polyunsaturated fatty acids such as arachidonic acid and docosahexaenoic acid also cause α-helical conformational change in α-synuclein but are believed to accelerate its aggregation. Up to date, the stably folded α-synuclein, which is believed crucial for its physiological function, remains elusive.

In the present work, we find oleic acid, one of the most abundant unsaturated fatty acid in vivo, induces an oligomeric α-helical structure with high stability. This unique stable oligomeric structure differs from the oligomers with a ß-sheet structure, the intermediate of amyloid fibrils. Thioflavin T fluorescence assay and transmission electron microscope shows its high resistance to aggregation. Revealed by circular dichroism titration, native gel electrophoresis and isothermal titration calorimetry, α-synuclein binds oleic acid with high affinity that may maintain the α-helical structure and inhibit the misfolding of protein. A two-step mechanism is found for the α-helical structure transition induced by fatty acid. An entropy-driven, endothermic interaction with the unsaturated fatty acid is found to precede the α-helical structural transition and prepare the protein for its interaction with negatively charged membrane surface. Finally, co-crystallization of α-synuclein with oleic acid was conducted in an attempt to obtain its structure.

This ordered oligomeric structure and fibrillization resistance suggests that the stable functional state of α-synuclein may be associated with oleic acid. These findings shed a new light on the native state of α-synuclein and help us understand its disease-related aggregation process.