Sucic Sonja, Kasture Ameya, Mazhar Asjad H M, Kern Carina, El-Kasaby Ali, Freissmuth Michael
Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria.
J Neurol Neuromedicine. 2016 Dec 30;1(9):34-40. doi: 10.29245/2572.942x/2016/9.1098.
The human dopamine transporter (hDAT) belongs to the solute carrier 6 (SLC6) gene family. Point mutations in hDAT (SLC6A3) have been linked to a syndrome of dopamine transporter deficiency or infantile dystonia/parkinsonism. The mutations impair DAT folding, causing retention of variant DATs in the endoplasmic reticulum and subsequently impair transport activity. The folding trajectory of DAT itself is not understood, though many insights have been gained from studies of folding-deficient mutants of the closely related serotonin transporter (SERT); i.e. their functional rescue by pharmacochaperoning with (nor)ibogaine or heat-shock protein inhibitors. We recently provided a proof-of-principle that folding-deficits in DAT are amenable to rescue and . As a model we used the Drosophila melanogaster DAT mutant dDAT-G108Q, which phenocopies the fumin/sleepless DAT-knockout. Treatment with noribogaine and/or HSP70 inhibitor pifithrin-μ restored folding of, and dopamine transport by, dDAT-G108Q, its axonal delivery and normal sleep time in mutant flies. The possibility of functional rescue of misfolded DATs in living flies by pharmacochaperoning grants new therapeutic prospects in the remedy of folding diseases, not only in hDAT, but also in other SLC6 transporters, in particular mutants of the creatine transporter-1, which give rise to X-linked mental retardation.
人类多巴胺转运体（hDAT）属于溶质载体6（SLC6）基因家族。hDAT（SLC6A3）中的点突变与多巴胺转运体缺乏综合征或婴儿肌张力障碍/帕金森症有关。这些突变会损害DAT的折叠，导致变异型DAT在内质网中滞留，进而损害转运活性。尽管通过对密切相关的5-羟色胺转运体（SERT）的折叠缺陷突变体的研究已获得了许多见解，但DAT自身的折叠轨迹仍不清楚；也就是说，通过与（去甲）伊博格碱或热休克蛋白抑制剂进行药物伴侣疗法可实现对其功能的挽救。我们最近提供了一个原理证明，即DAT的折叠缺陷是可以挽救的。作为一个模型，我们使用了果蝇多巴胺转运体突变体dDAT-G108Q，它模拟了fumin/sleepless多巴胺转运体基因敲除的表型。用去甲伊博格碱和/或热休克蛋白70（HSP70）抑制剂匹非尼酮-μ进行处理，可恢复dDAT-G108Q的折叠、多巴胺转运、轴突运输，并使突变果蝇的睡眠时间恢复正常。通过药物伴侣疗法在活果蝇中对错误折叠的DAT进行功能挽救的可能性，为折叠疾病的治疗带来了新的治疗前景，不仅适用于hDAT，也适用于其他SLC6转运体，特别是肌酸转运体-1的突变体，这些突变体会导致X连锁智力迟钝。
