Behavioral and neurochemical studies of inherited manganese-induced dystonia-parkinsonism in Slc39a14-knockout mice.
Behavioral and neurochemical studies of inherited manganese-induced dystonia-parkinsonism in Slc39a14-knockout mice.
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DOI：
10.1016/j.nbd.2021.105467
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发表时间：
2021-10
影响因子：
6.1
通讯作者：
Guilarte TR
中科院分区：
文献类型：
--
作者：
Rodichkin AN;Edler MK;McGlothan JL;Guilarte TR
人类锰 (Mn) 转运蛋白基因 SLC39A14 的遗传性常染色体隐性突变会导致血液和大脑中锰浓度升高以及儿童期发病的肌张力障碍-帕金森症。这种疾病的病理生理学尚不清楚，但与基底神经节的黑质纹状体多巴胺能系统有关。在这里，我们描述了 Slc39a14 敲除（KO）小鼠的病理生理学研究，作为 SLC39A14 突变携带者肌张力障碍帕金森病的临床前模型。 Slc39a14-KO 小鼠的血液和脑金属浓度表现出与人类疾病相似的模式，锰浓度高度升高。我们在出生后第 21 天（PN）观察到早发的向后行走行为，这在 PN60 Slc39a14-KO 小鼠以及肌张力障碍样运动中也被注意到。相对于野生型 (WT) 小鼠，Slc39a14-KO 小鼠的运动活动和运动协调性也受到损害。从神经化学角度来看，Slc39a14-KO 小鼠的纹状体多巴胺 (DA) 和代谢物浓度及其比例与 WT 没有差异。相对于 WT，Slc39a14-KO 小鼠的纹状体酪氨酸羟化酶 (TH) 免疫组织化学没有变化。 Slc39a14-KO 小鼠黑质致密部 (SNc) 中 TH 阳性和尼氏染色估计神经元数量、神经元密度和体细胞体积的无偏立体学细胞定量与 WT 相同。然而，我们测量到 Slc39a14-KO 小鼠纹状体中钾刺激的 DA 释放相对于 WT 有显着抑制（85-90%）。我们的研究结果表明，在人类疾病的遗传动物模型中观察到的肌张力障碍-帕金森症与功能失调但结构完整的黑质纹状体多巴胺能系统有关。 DA 释放的突触前缺陷不太可能解释整个行为表型，并表明其他神经元系统和大脑区域参与了该疾病的病理生理学。
Inherited autosomal recessive mutations of the manganese (Mn) transporter gene SLC39A14 in humans, results in elevated blood and brain Mn concentrations and childhood-onset dystonia-parkinsonism. The pathophysiology of this disease is unknown, but the nigrostriatal dopaminergic system of the basal ganglia has been implicated. Here, we describe pathophysiological studies in Slc39a14-knockout (KO) mice as a preclinical model of dystonia-parkinsonism in SLC39A14 mutation carriers. Blood and brain metal concentrations in Slc39a14-KO mice exhibited a pattern similar to the human disease with highly elevated Mn concentrations. We observed an early-onset backward-walking behavior at postnatal day (PN) 21 which was also noted in PN60 Slc39a14-KO mice as well as dystonia-like movements. Locomotor activity and motor coordination were also impaired in Slc39a14-KO relative to wildtype (WT) mice. From a neurochemical perspective, striatal dopamine (DA) and metabolite concentrations and their ratio in Slc39a14-KO mice did not differ from WT. Striatal tyrosine hydroxylase (TH) immunohistochemistry did not change in Slc39a14-KO mice relative to WT. Unbiased stereological cell quantification of TH-positive and Nissl-stained estimated neuron number, neuron density, and soma volume in the substantia nigra pars compacta (SNc) was the same in Slc39a14-KO mice as in WT. However, we measured a marked inhibition (85–90%) of potassium-stimulated DA release in the striatum of Slc39a14-KO mice relative to WT. Our findings indicate that the dystonia-parkinsonism observed in this genetic animal model of the human disease is associated with a dysfunctional but structurally intact nigrostriatal dopaminergic system. The presynaptic deficit in DA release is unlikely to explain the totality of the behavioral phenotype and points to the involvement of other neuronal systems and brain regions in the pathophysiology of the disease.
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DOI：
10.1073/pnas.0810599106
发表时间：
2009-04-21
影响因子：
11.1
作者：
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影响因子：
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