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Hyperphosphorylation of the Parkinson’s Disease protein α-Synuclein increases the rate of neurotoxic fibril formation in vitro
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|Title:||Hyperphosphorylation of the Parkinson’s Disease protein α-Synuclein increases the rate of neurotoxic fibril formation in vitro|
|Contributors:||James, Nicholas (advisor)|
Department of Cell and Molecular Biology and Chemistry (department)
|Publisher:||University of Hawaii at Manoa|
|Abstract:||Parkinson’s disease is a neurological disease that affects approximately 3% of the
population over the age of 60 and is the second most common neurodegenerative disorder. PD
is characterized by reduced levels of dopamine in the brain due to neuronal death in the
substantia nigra. The surviving neurons contain spherical inclusions called Lewy Bodies (LBs)
that are composed of a dense aggregation of proteins and lipids. α-Synuclein (aSyn) is the
primary protein component of LB’s. Alterations in the expression of aSyn have been shown to
affect neurotransmitter (such as dopamine) release. Also, when incubated at 37° C aSyn
spontaneously forms fibril structures demonstrating the importance of this protein in LB
Hyperphosphorylated aSyn is the major fraction of protein found in LBs. This research
project investigated the role of phosphorylation in aSyn aggregation in order to gain insight into
the molecular basis of PD. S129E aSyn is a mutation that mimics phosphorylation at serine 129.
In this project, wild-type aSyn and S129E aSyn were expressed and purified, and the rate of
fibril formation was compared using a Thioflavin T fluorescence assay. The Thioflavin T assay
showed a threefold increase in the rate of fibril formation in the S129E aSyn, consistent with a
disease model in which hyper-phosphorylated aSyn increases the likelihood of formation of
neurotoxic fibrils. The confirmation of the importance of phosphorylation in LB formation
provides a molecular basis into the pathogenesis of PD and suggests further research on protein
kinases that phosphorylate aSyn as a promising area of future research.
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Honors Projects for Biochemistry|
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