Dopamine Transporter Activity Is Modulated by α-synuclein

Abstract

The duration and strength of the dopaminergic signal is regulated by the dopamine transporter (DAT). Drug addiction, neurodegenerative and neuropsychiatric diseases have all been associated with altered DAT activity. The membrane localization and the activity of DAT are regulated by a number of intracellular proteins. α-synuclein, a protein partner of DAT, is implicated in neurodegenerative disease and drug addiction. Little is known about the regulatory mechanisms of the interaction between DAT and α-synuclein, the cellular location of this interaction, and the functional consequences of this interaction on the basal, amphetamine (AMPH) induced DAT-meditated DA efflux and membrane microdomain distribution of the transporter. Here, we found that the majority of DAT/α-synuclein protein complexes are found at the plasma membrane of dopaminergic neurons or mammalian cells, and that AMPH-mediated increase in DAT activity enhances the association of these proteins at the plasma membrane. Further examination of the interaction of DAT and α-synuclein revealed a transient interaction between these two proteins at the plasma membrane. Additionally, we found DAT-induced membrane depolarization enhances plasma membrane localization of α-synuclein, which in turn increases DA efflux and enhances DAT localization in cholesterol rich membrane microdomains.

How can rAAV‐α‐synuclein and the fibril α‐synuclein models advance our understanding of Parkinson's disease?

“…All of these changes occur before the onset of dopaminergic cell death and suggest that synaptic and axonal defects contribute to the development of PD symptoms well before neuron death ensues. A recent study suggests that the dopamine transporter and a-synuclein interact at the cell surface, and abnormal a-synuclein may influence the activity of the dopamine transporter, causing these early changes in dopaminergic activity (Butler et al 2015). The rapid early loss of striatal dopamine function seen in the rAAV-a-synuclein model replicates the pattern seen in human disease.…”

“…A recent study suggests that the dopamine transporter and α‐synuclein interact at the cell surface, and abnormal α‐synuclein may influence the activity of the dopamine transporter, causing these early changes in dopaminergic activity (Butler et al . ). The rapid early loss of striatal dopamine function seen in the rAAV‐α‐synuclein model replicates the pattern seen in human disease.…”

Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact

“…Surface DAT is distributed among several membrane microdomains (Adkins et al 2007;Navaroli et al 2011;Cremona et al 2011;Butler et al 2015;Kovtun et al 2015;…”

Synaptic failure and α‐synuclein

“…This function is implicated in neurotransmitter release; indeed, a number of studies have shown that mice lacking all 3 members of the synuclein family (α,β,ɣ‐synucleins) or of αSYN alone exhibit an increase in the rate of induced DA release whereas an overexpression of αSYN decreased the levels of striatal DA release . In addition to a role in DA release, there is also convincing evidence to suggest that αSYN promotes vesicle filling through direct interaction and modulation of the vesicular monoamine transporter 2 (VMAT2) as well as the reuptake of dopamine (DA) via the dopamine transporter (DAT), further supporting the notion that αSYN is a general modulator of DA homeostasis …”