Direct binding and functional coupling of α-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis

Abstract

Mutations in alpha-synuclein, a protein highly enriched in presynaptic terminals, have been implicated in the expression of familial forms of Parkinson's disease (PD) whereas native alpha-synuclein is a major component of intraneuronal inclusion bodies characteristic of PD and other neurodegenerative disorders. Although overexpression of human alpha-synuclein induces dopaminergic nerve terminal degeneration, the molecular mechanism by which alpha-synuclein contributes to the degeneration of these pathways remains enigmatic. We report here that alpha-synuclein complexes with the presynaptic human dopamine transporter (hDAT) in both neurons and cotransfected cells through the direct binding of the non-A beta amyloid component of alpha-synuclein to the carboxyl-terminal tail of the hDAT. alpha-Synuclein--hDAT complex formation facilitates the membrane clustering of the DAT, thereby accelerating cellular dopamine uptake and dopamine-induced cellular apoptosis. Since the selective vulnerability of dopaminergic neurons in PD has been ascribed in part to oxidative stress as a result of the cellular overaccumulation of dopamine or dopamine-like molecules by the presynaptic DAT, these data provide mechanistic insight into the mode by which the activity of these two proteins may give rise to this process.

Dopamine Transporter Activity Is Modulated by α-Synuclein

“…The dynamic "on" and "off," interaction mode between DAT and ␣-synuclein provides an opportunity for other regulatory proteins to interact with the C terminus of DAT (66). For example, CaMKII␣ and ␣-synuclein interact with the C terminus of DAT (residues 597-620 for ␣-synuclein (12) and 598 -620 for CaMKII␣ (9)) and influence the activity of DAT (9,12). Therefore, at the physiological level of ␣-synuclein the balanced competition between CaMKII␣ and ␣-synuclein for a shared binding domain on the C terminus of DAT regulates the function of DAT.…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Moreover, direct binding and functional coupling of alphaͲsyn to the dopamine transporter (DAT, responsible for the reͲuptake of this neurotransmitter from the synaptic cleft) was reported to accelerate dopamine uptake, increasing dopamine levels in the cytosol and dopamineͲinduced apoptosis [130].…”

Parkinson's Disease-associated α-Synuclein Is a Calmodulin Substrate

“…Several proteins have been proposed to be synuclein interactors (41,42). In transfection experiments, synphillin (43), an ␣-synuclein interactor identified in a yeast two-hybrid screen, promoted formation of NAC (a peptide derived from synuclein) aggregates.…”