The dopamine transporter is differentially regulated after dopaminergic lesion

被引:27
作者
Afonso-Oramas, Domingo [1 ]
Cruz-Muros, Ignacio [1 ,5 ]
Barroso-Chinea, Pedro [2 ,5 ]
Alvarez de la Rosa, Diego [3 ]
Castro-Hernandez, Javier [1 ]
Salas-Hernandez, Josmar [1 ]
Giraldez, Teresa [4 ]
Gonzalez-Hernandez, Tomas [1 ,5 ]
机构
[1] Univ La Laguna, Fac Med, Dept Anat, Tenerife 38207, Spain
[2] Univ Navarra, Ctr Invest Med Aplicada, E-31080 Pamplona, Spain
[3] Univ La Laguna, Fac Med, Dept Fisiol, Tenerife 38207, Spain
[4] Hosp Univ Ntra Sra Candelaria, Unidad Invest, Tenerife, Spain
[5] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
关键词
Parkinson's disease; Vulnerability; Mesostriatal; Degeneration; Dopamine transporter; Rat; HEK-cell; 6-OHDA; MPP+; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; NEUROTRANSMITTER TRANSPORTERS; COMPARTMENTAL ORGANIZATION; NEURONAL DEGENERATION; MPTP NEUROTOXICITY; ENERGY-METABOLISM; XENOPUS OOCYTES; MESSENGER-RNA; ANIMAL-MODELS;
D O I
10.1016/j.nbd.2010.07.012
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 DA-terminals, 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 HEM 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. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:518 / 530
页数:13
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