The dopamine transporter is differentially regulated after dopaminergic lesion
Fecha
2010Resumen
The dopamine transporter (DAT) is a transmembrane glycoprotein responsible for dopamine (DA) uptake,
which has been shown to be involved in DA-cell degeneration in Parkinson's disease (PD). At the same time,
some studies suggest that DAT may be regulated in response to dopaminergic injury. We have investigated
the mechanisms underlying DAT regulation after different degrees of dopaminergic lesion. DAT is
persistently down-regulated in surviving midbrain DA-neurons after substantial (62%) loss of striatal DAterminals, and transiently after slight (11%) loss of DA-terminals in rats. Transient DAT down-regulation
consisted of a decrease of glycosylated (mature) DAT in the plasma membrane with accumulation of nonglycosylated (immature) DAT in the endoplasmic reticulum-Golgi (ERG) compartment, and recovery of the
normal expression pattern 5 days after lesion. DAT redistribution to the ERG was also observed in HEK cells
expressing rat DAT exposed to MPP+, but not after exposure to DAT-unrelated neurotoxins. In contrast to
other midbrain DA-cells, those in the ventrolateral region of the substantia nigra do not regulate DAT and
degenerate shortly after slight DA-lesion. These data suggest that DAT down-regulation is a post-traslational
event induced by DA-analogue toxins, consisting of a stop in its glycosylation and trafficking to the plasma
membrane. Its persistence after substantial DA-lesion may act as a compensatory mechanism helping
maintain striatal DA levels. The fact that neurons which do not regulate DAT die shortly after lesion suggests
a relationship between DAT down-regulation and neuroprotection.