Attenuation of dopamine transporter activity by alpha-synuclein.
Alpha-synuclein accumulates in Lewy bodies in idiopathic Parkinson's disease. Neither the normal function nor contribution of alpha-synuclein to the pathophysiology of neurodegeneration is known. Here we show that a normal function of alpha-synuclein is the negative modulation of human dopamine transporter (hDAT) activity. In cotransfected Ltk(-) cells, alpha-synuclein attenuated the reuptake of dopamine by hDAT, in a manner dependent on expression levels of alpha-synuclein. Alpha-synuclein-mediated inhibition of hDAT activity was independent of expression vectors, cell types and methods of transfection. The alpha-synuclein-mediated decrease in DAT activity occurred through diminished uptake velocity of dopamine, without changes in the affinity of hDAT for dopamine. Co-immunoprecipitation studies confirmed the formation of a stable complex between alpha-synuclein and DAT, through direct protein:protein interactions. Thus, under normal (non-toxic) expression conditions, alpha-synuclein negatively modulates dopamine uptake by DAT.
Wersinger
Christophe
C
Department of Pediatrics, Georgetown University, Washington, DC 20007, USA.
Sidhu
Anita
A
D000818:Animals; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D051843:Synucleins; D051844:alpha-Synuclein
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; C497604:SNCA protein, human; C493215:Slc6a3 protein, mouse; C493216:Slc6a3 protein, rat; C497605:Snca protein, mouse; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; D004298:Dopamine