Dopamine transporter glycosylation correlates with the vulnerability of midbrain dopaminergic cells in Parkinson's disease
Fecha
2009Resumen
The dopamine transporter (DAT) is a membrane glycoprotein responsible for dopamine (DA) uptake, which
has been involved in the degeneration of DA cells in Parkinson's disease (PD). Given that DAT activity
depends on its glycosylation status and membrane expression, and that not all midbrain DA cells show the
same susceptibility to degeneration in PD, we have investigated a possible relationship between DAT
glycosylation and function and the differential vulnerability of DA cells. Glycosylated DAT expression, DA
uptake, and DAT Vmax were significantly higher in terminals of nigrostriatal neurons than in those of
mesolimbic neurons. No differences were found in non-glycosylated DAT expression and DAT Km, and DA
uptake differences disappeared after deglycosylation of nigrostriatal synaptosomes. The expression pattern
of glycosylated DAT in the human midbrain and striatum showed a close anatomical relationship with DA
degeneration in parkinsonian patients. This relationship was confirmed in rodent and monkey models of PD,
and in HEK cells expressing the wild-type and a partially deglycosylated DAT form. These results strongly
suggest that DAT glycosylation is involved in the differential vulnerability of midbrain DA cells in PD.