Wang Guangliang, Zhang Guoqiang, Li Zhuyun, Fawcett Caroline H, Coble Matthew, Sosa Maria X, Tsai Tingwei, Malesky Kimberly, Thibodeaux Stefan J, Zhu Peixin, Glass David J, Fishman Mark C
Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
iScience. 2019 Jul 26;17:325-333. doi: 10.1016/j.isci.2019.06.039. Epub 2019 Jul 4.
Dopamine transporter (SLC6A3) deficiency causes infantile Parkinson disease, for which there is no effective therapy. We have explored the effects of genetically deleting SLC6A3 in zebrafish. Unlike the wild-type, slc6a3-/- fish hover near the tank bottom, with a repetitive digging-like behavior. slc6a3-/- fish manifest pruning and cellular loss of particular tyrosine hydroxylase-immunoreactive neurons in the midbrain. Clozapine, an effective therapeutic for treatment-resistant schizophrenia, rescues the abnormal behavior of slc6a3-/- fish. Clozapine also reverses the abnormalities in the A8 region of the mutant midbrain. By RNA sequencing analysis, clozapine increases the expression of erythropoietin pathway genes. Transgenic over-expression of erythropoietin in neurons of slc6a3-/- fish partially rescues the mutant behavior, suggesting a potential mechanistic basis for clozapine's efficacy.
多巴胺转运体（SLC6A3）缺乏会导致婴儿帕金森病，目前尚无有效治疗方法。我们研究了在斑马鱼中基因敲除SLC6A3的影响。与野生型不同，slc6a3-/- 斑马鱼在水箱底部附近盘旋，伴有类似反复挖掘的行为。slc6a3-/- 斑马鱼中脑特定酪氨酸羟化酶免疫反应性神经元出现修剪和细胞丢失。氯氮平是一种治疗难治性精神分裂症的有效药物，可挽救slc6a3-/- 斑马鱼的异常行为。氯氮平还可逆转突变体中脑A8区域的异常。通过RNA测序分析，氯氮平可增加促红细胞生成素途径基因的表达。在slc6a3-/- 斑马鱼的神经元中过表达促红细胞生成素可部分挽救突变行为，这表明氯氮平疗效的潜在机制基础。
