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Striatal dopamine transporter function is facilitated by converging biology of α-synuclein and cholesterol

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. and Brimblecombe, Katherine R. 2021. Striatal dopamine transporter function is facilitated by converging biology of α-synuclein and cholesterol. Frontiers in Cellular Neuroscience 15 , 658244. 10.3389/fncel.2021.658244

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Abstract

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 (SNCA-OVX) transgenic mouse model of early PD. Using fast-scan cyclic voltammetry (FCV) in ex vivo acute striatal slices to detect DA release, and biochemical assays, we show that several aspects of DAT function are promoted in SNCA-OVX mice. Compared to background control α-synuclein-null mice (Snca-null), the SNCA-OVX mice have elevated DA uptake rates, and more pronounced effects of DAT inhibitors on evoked extracellular DA concentrations ([DA]o) 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 Snca-null and SNCA-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 SNCA-OVX mice. An inhibitor of cholesterol efflux transporter ABCA1 or a cholesterol chelator in SNCA-OVX mice reduced the effects of DAT-inhibitors on evoked [DA]o. 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Frontiers Media
ISSN: 1662-5102
Date of First Compliant Deposit: 25 June 2021
Date of Acceptance: 22 March 2021
Last Modified: 25 Jun 2021 15:30
URI: https://orca.cardiff.ac.uk/id/eprint/142158

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