Pathological accumulation of misfolded α-synuclein (α-syn) in the brain plays a key role in the pathogenesis of Parkinson's disease, leading to neuronal dysfunction and motor disorders. The underlying mechanisms linking α-syn aggregations with neurotransmitter disturbance in Parkinson's brains are not well characterized. In the present study, we investigated transgenic mice expressing an aggregation-prone form of full-length human α-syn (h-α-synL62) linked to a signal sequence. These mice display dopamine depletion and progressive motor deficits. We detected accumulation of α-syn in cholinergic interneurons where they are colocalized with choline acetyltransferase. Using microdialysis, we measured acetylcholine levels in the striatum at baseline and during stimulation in the open field and with scopolamine. While no difference between wild-type and transgenic mice was detected in 3 month old mice, striatal acetylcholine levels at 9 months of age were significantly higher in transgenic mice. Concomitantly, high-affinity choline uptake was also increased while choline acetyltransferase and acetylcholine esterase activities were unchanged. The results suggest a disinhibition of acetylcholine release in α-syn transgenic mice.

中文翻译：

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增加的α-突触核蛋白转基因小鼠（h-α-synL62）的胆碱能反应。

脑中错误折叠的α-突触核蛋白（α-syn）的病理积累在帕金森氏病的发病机理中起关键作用，导致神经元功能障碍和运动障碍。帕金森氏大脑中将α-syn聚集体与神经递质紊乱联系起来的潜在机制尚不清楚。在本研究中，我们调查了转基因小鼠表达易于聚集的全长人α-syn（h-α-synL62）与信号序列连接的形式。这些小鼠表现出多巴胺耗竭和进行性运动障碍。我们检测到胆碱能神经元中与胆碱乙酰转移酶共定位的α-syn的积累。使用微透析，我们在基线以及在空旷地区和东碱刺激期间测量纹状体中乙酰胆碱的水平。尽管在3个月大的小鼠中未检测到野生型和转基因小鼠之间的差异，但在9个月大的小鼠中，纹状体乙酰胆碱水平明显高于转基因小鼠。同时，高亲和力的胆碱摄取也增加了，而胆碱乙酰转移酶和乙酰胆碱酯酶活性没有改变。结果表明在α-syn转基因小鼠中乙酰胆碱释放的抑制作用。