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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons
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Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons

机译：黑质多巴胺神经元中α-突触核蛋白过表达导致神经传递受损

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摘要

We used in vivo amperometry to monitor changes in synaptic dopamine (DA) release in the striatum induced by overexpression of human wild-type α-synuclein in nigral DA neurons, induced by injection of an adeno-associated virus type 6 (AAV6)-α-synuclein vector unilaterally into the substantia nigra in adult rats. Impairments in DA release evolved in parallel with the development of degenerative changes in the nigrostriatal axons and terminals. The earliest change, seen 10 d after vector injection, was a marked, ≈50%, reduction in DA reuptake, consistent with an early dysfunction of the DA transporter that developed before any overt signs of axonal damage. At 3 wk, when the first signs of axonal damage were observed, the amount of DA released after a KCI pulse was reduced by 70-80%, and peak DA concentration was delayed, indicating an impaired release mechanism. At later time points, 8-16 wk, overall striatal innervation density was reduced by 60-80% and accompanied by abundant signs of axonal damage in the form of α-synuclein aggregates, axonal swellings, and dystrophic axonal profiles. At this stage DA release and reuptake were profoundly reduced, by 80-90%. The early changes in synaptic DA release induced by overexpression of human a-synuclein support the idea that early predegenerative changes in the handling of DA may initiate, and drive, a progressive degenerative process that hits the axons and terminals first. Synaptic dysfunction and axon-opathy would thus be the hallmark of presymptomatic and early-stage Parkinson disease, followed by neuronal degeneration and cell loss, characteristic of more advanced stages of the disease.
机译：我们使用体内安培法来监测由人野生型α-突触核蛋白在黑质DA神经元中的过表达诱导的纹状体多巴胺（DA）释放的变化，该过程通过注射腺伴随病毒6型（AAV6）-α诱导-突触核蛋白载体单侧进入成年大鼠的黑质。 DA释放的损害与黑质纹状体轴突和末端的退行性变化的发展同时发生。最早的变化是在载体注射后10 d出现的，DA吸收显着降低了≈50％，这与在任何明显的轴突损伤迹象之前发展的DA转运蛋白的早期功能障碍相一致。在3周时，当观察到轴突损伤的最初迹象时，KCI脉冲后释放的DA量减少了70-80％，峰值DA浓度被延迟，表明释放机制受损。在随后的时间点（8-16周），总体纹状体神经支配密度降低了60-80％，并伴随着以α-突触核蛋白聚集体，轴突肿胀和营养不良的轴突轮廓形式出现的大量轴突损伤迹象。在这一阶段，DA的释放和再摄取被大大降低了80-90％。由人α-突触核蛋白的过表达诱导的突触DA释放的早期变化支持这样的想法，即DA处理中的早期变性前的变化可以引发并驱动渐进的变性过程，该过程首先打击轴突和末端。因此，突触功能障碍和轴突病将成为症状前和早期帕金森病的标志，其次是神经元变性和细胞丢失，这是该病更晚期的特征。

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