AUTHOR=Threlfell Sarah , Mohammadi Amir Saeid , Ryan Brent J. , Connor-Robson Natalie , Platt Nicola J. , Anand Rishi , Serres Florence , Sharp Trevor , Bengoa-Vergniory Nora , Wade-Martins Richard , Ewing Andrew , Cragg Stephanie J. , Brimblecombe Katherine R. 

TITLE=Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of α-Synuclein and Cholesterol

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=15

YEAR=2021

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2021.658244

DOI=10.3389/fncel.2021.658244

ISSN=1662-5102

ABSTRACT=<p>Striatal dopamine transporters (DAT) powerfully regulate dopamine signaling, and can contribute risk to degeneration in Parkinson’s disease (PD). DATs can interact with the neuronal protein α-synuclein, which is associated with the etiology and molecular pathology of idiopathic and familial PD. Here, we tested whether DAT function in governing dopamine (DA) uptake and release is modified in a human-α-synuclein-overexpressing (<italic>SNCA</italic>-OVX) transgenic mouse model of early PD. Using fast-scan cyclic voltammetry (FCV) in <italic>ex vivo</italic> acute striatal slices to detect DA release, and biochemical assays, we show that several aspects of DAT function are promoted in <italic>SNCA</italic>-OVX mice. Compared to background control α-synuclein-null mice (<italic>Snca</italic>-null), the <italic>SNCA</italic>-OVX mice have elevated DA uptake rates, and more pronounced effects of DAT inhibitors on evoked extracellular DA concentrations ([DA]<sub>o</sub>) and on short-term plasticity (STP) in DA release, indicating DATs play a greater role in limiting DA release and in driving STP. We found that DAT membrane levels and radioligand binding sites correlated with α-synuclein level. Furthermore, DAT function in <italic>Snca</italic>-null and <italic>SNCA</italic>-OVX mice could also be promoted by applying cholesterol, and using Tof-SIMS we found genotype-differences in striatal lipids, with lower striatal cholesterol in <italic>SNCA</italic>-OVX mice. An inhibitor of cholesterol efflux transporter ABCA1 or a cholesterol chelator in <italic>SNCA</italic>-OVX mice reduced the effects of DAT-inhibitors on evoked [DA]<sub>o</sub>. Together these data indicate that human α-synuclein in a mouse model of PD promotes striatal DAT function, in a manner supported by extracellular cholesterol, suggesting converging biology of α-synuclein and cholesterol that regulates DAT function and could impact DA function and PD pathophysiology.</p>