Dopamine transporter glycosylation correlates with the vulnerability of midbrain dopaminergic cells in Parkinson's disease.
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 V(max) 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 K(m), 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.
Afonso-Oramas
Domingo
D
Departamento de Anatomía, Facultad de Medicina, Universidad de La Laguna, Tenerife, Spain.
Cruz-Muros
Ignacio
I
Alvarez de la Rosa
Diego
D
Abreu
Pedro
P
Giráldez
Teresa
T
Castro-Hernández
Javier
J
Salas-Hernández
Josmar
J
Lanciego
José L
JL
Rodríguez
Manuel
M
González-Hernández
Tomas
T
D000368:Aged; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005260:Female; D006031:Glycosylation; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008636:Mesencephalon / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D050483:Dopamine Plasma Membrane Transport Proteins; D004298:Dopamine