THESIS
2017
xxiii, 254 pages : illustrations (some color) ; 30 cm
Abstract
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...[
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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.
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