Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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 ORCID: https://orcid.org/0000-0001-8350-6928, 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

[thumbnail of fncel-15-658244.pdf] PDF - Published Version
Available under License Creative Commons Attribution.

Download (2MB)

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: 10 May 2023 02:12
URI: https://orca.cardiff.ac.uk/id/eprint/142158

Citation Data

Cited 11 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics