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Regulation of Dopamine Transporter Function and Trafficking by Atorvastatin in Neuroblastoma N2a cells

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title
Regulation of Dopamine Transporter Function and Trafficking by Atorvastatin in Neuroblastoma N2a cells
author
Wang, Shiyu
abstract
Dopamine (DA), one of the major neurotransmitters in the brain, regulates many aspects of brain functions including working memory, movement, and reward. The termination of DA signaling is carried out by DA transporter (DAT), which removes the synaptic DA by reuptake them to presynaptic DAergic neurons. Dysregulation of DAT has been implicated in several neurological and psychiatric diseases including Alzheimer's disease, Parkinson’s disease, and substance abuse disorder. Thus, it is important to understand the molecular and cellular mechanisms underlying dysfunctional DAT. Membrane cholesterol is highly associated with the function of DAT. Depletion of membrane cholesterol by methyl-β-cyclodextrin reduces DAT uptake. This is of particular interest because a few statin drugs that are commonly used for treating hypercholesterolemia are blood-brain-barrier permeable and thus could alter brain cholesterol homeostasis and impact DAT function. The current study investigates the effects of atorvastatin, a commonly prescribed statin, on the function of DAT in neuroblastoma 2A cells stably expressing human DAT. We found that atorvastatin treatment dose-dependently reduced membrane cholesterol levels and DA uptake via DAT. Furthermore, this effect is mediated through two different mechanisms. Atorvastatin treatment reduced membrane cholesterol, altering DAT binding to cocaine. On the other hand, statins also cause a shift in actin dynamics, which impairs the normal trafficking of DAT. This project highlights the importance of cholesterol-DAT interaction and provides evidence for repurposing statins as potential treatment for Alzheimer's disease, Parkinson’s disease, and substance abuse disorder.
subject
Actin Skeleton
Addiction
Cholesterol
Dopamine Transporter
Statins
contributor
Reid, Ke Z (committee chair)
Chen, Rong (committee member)
Howlett , Allyn C (committee member)
date
2021-06-03T08:36:19Z (accessioned)
2021 (issued)
degree
Biomedical Science – MS (discipline)
embargo
2026-05-17 (terms)
2026-05-17 (liftdate)
identifier
http://hdl.handle.net/10339/98836 (uri)
language
en (iso)
publisher
Wake Forest University
type
Thesis

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