Expression of dopamine and vesicular monoamine transporters and differential vulnerability of mesostriatal dopaminergic neurons

Abstract

Numerous studies suggest that the dopamine transporter (DAT), responsible for dopamine reuptake, may act as a vulnerability factor in the pathogenesis of Parkinson's disease (PD) and the vesicular monoamine transporter (VMAT2), responsible for its vesicular storage, as a neuroprotective factor. However, the relevance of each on the differential vulnerability of midbrain DA cells remains unknown. Here we studied the relationship between the expression pattern (mRNA and protein) of both transporters and the differential vulnerability of midbrain DA cells in a model of PD (intracerebroventricular injection of 6-OHDA in rats) and in monkey and human midbrain. Our results revealed that the expression patterns for VMAT2 mRNA and protein and DAT mRNA are similar, with the highest levels in the rostromedial region of substantia nigra (SNrm), followed by the caudoventral region of SN (SNcv), the ventral tegmental area and pigmented parabrabraquial nucleus (VTA/PBP), and finally the linear and interfascicular nuclei (Li/IF). In contrast, the expression of DAT protein in rats, monkeys, and humans followed a caudoventrolateral-to-rostrodorsomedial decreasing gradient (SNcv > SNrm > VTA/PBP > Li/IF), matching the degeneration profile observed after intracerebroventricular injection of 6-OHDA and in PD. In addition, DAT blockade made all midbrain DA cells equally resistant to 6-OHDA. These data indicate that DAT protein levels, but not DAT mRNA levels, are closely related to the differential vulnerability of midbrain DA cells and that this relationship is unaffected by the relative levels of VMAT2. Furthermore, the difference between DAT mRNA and protein profiles suggests internuclear differences in its posttransductional regulation.

Dual effects of TNFα on nerve fiber formation from ventral mesencephalic organotypic tissue cultures

“…It is well known that A9 dopamine neurons are more vulnerable to toxic insults than A10 neurons (Barroso-Chinea et al 2005;Gibb 1992;Gonzalo-Hernandez et al 2004;Kish et al 1988). It cannot be determined from this study whether TNFα treatment affected specifically A9 or A10 dopamine neurons.…”

RA Differentiation Enhances Dopaminergic Features, Changes Redox Parameters, and Increases Dopamine Transporter Dependency in 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells

“…It is widely elucidate that 6-OHDA is taken up by dopaminergic neurons via DAT (Tranzer and Thoenen 1973) and auto-oxidation process occurs intracellularly (Glinka et al 1997) manly because the toxicity can be blocked by DAT inhibition (González-Hernández et al 2004). On the other hand, previous data have shown that 6-OHDA uptake is not an essential process and the autooxidation occurs extracellularly in undifferentiated cells (Izumi et al 2005).…”

A Specific Survival Response in Dopamine Neurons at Most Risk in Parkinson's Disease

“…These neurons are at particular risk in PD, whereas DA neurons in ventral tegmental area (or A10) are predominantly calbindin ϩ (Gerfen et al, 1987). In both rodent and primate adult midbrain, the levels of DAT mRNA (Sanghera et al, 1994;Haber et al, 1995) and DAT protein (Gonzalez-Hernandez et al, 2004) are higher in calbindin Ϫ than in calbindin ϩ DA neurons. In vivo studies both in rodents and primates show that the neurons of the rostromedial region of substantia nigra, the majority of which are calbindin ϩ , express higher level of VMAT2 than the caudoventral regions of substantia nigra, the majority of which are calbindin Ϫ (GonzalezHernandez et al, 2004).…”