Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of α-Synuclein and Cholesterol
Artikel i vetenskaplig tidskrift, 2021

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] ) 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] . 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.

cholesteroI

dopamine uptake

alpha-synuclein (SNCA)

Parkinson’s disease

dopamine transporter (DAT)

galactoceramide

striatum

early stage parkinsonism

Författare

Sarah Threlfell

University of Oxford

Amir Saeid Mohammadi

Chalmers, Kemi och kemiteknik, Kemi och biokemi, Analytisk kemi

Brent J. Ryan

University of Oxford

Natalie Connor-Robson

University of Oxford

Nicola J. Platt

University of Oxford

Rishi Anand

University of Oxford

Florence Serres

University of Oxford

Trevor Sharp

University of Oxford

Nora Bengoa-Vergniory

University of Oxford

Richard Wade-Martins

University of Oxford

Andrew Ewing

Göteborgs universitet

Stephanie J. Cragg

University of Oxford

Katherine R. Brimblecombe

University of Oxford

Frontiers in Cellular Neuroscience

1662-5102 (ISSN)

Vol. 15 658244

Ämneskategorier

Neurovetenskaper

Farmakologi och toxikologi

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

DOI

10.3389/fncel.2021.658244

PubMed

33935654

Mer information

Senast uppdaterat

2021-05-18