Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of α-synuclein neurotoxicity
Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of α-synuclein neurotoxicity
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DOI：
10.1016/j.neuron.2007.01.019
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发表时间：
2007-02-15
期刊：
影响因子：
16.2
通讯作者：
Kinoshita, Makoto
中科院分区：
文献类型：
--
作者：
Ihara, Masafumi;Yamasaki, Nobuyuki;Kinoshita, Makoto
在帕金森病 (PID) 中，称为路易体的 α-突触核蛋白聚集体通常涉及并隔离 Septin4 (Sept4)（一种聚合支架蛋白）。然而，这种现象的病理生理学意义尚不清楚。在这里，我们展示了 Sept4 与 α-突触核蛋白、多巴胺转运蛋白以及多巴胺能神经元中其他突触前蛋白的生理关联；缺乏 Sept4 的小鼠由于缺乏这些突触前蛋白而表现出多巴胺能神经传递减弱。这些数据证明了脓毒症支架在大脑中的重要作用。在表达人类 α-突触核蛋白 (A53T)（一种导致家族性 PD 的突变蛋白）的转基因小鼠中，Sept4 的缺失会显着增强神经病理学和运动能力恶化。在该PID模型中，Ser(129)-磷酸化α-突触核蛋白(A53T)的不溶性沉积物与Sept4的剂量呈负相关。在体外，与 Sept4 直接结合可保护 α-突触核蛋白免于自我聚集和 Ser(129) 磷酸化。总而言之，这些数据表明 Sept4 可能作为双重易感因素参与 PID，因为其不足会减少多巴胺能神经传递并增强 α-突触核蛋白神经毒性。
In Parkinson disease (PID), alpha-synuclein aggregates called Lewy bodies often involve and sequester Septin4 (Sept4), a polymerizing scaffold protein. However, the pathophysiological significance of this phenomenon is unclear. Here, we show the physiological association of Sept4 with alpha-synuclein, the dopamine transporter, and other presynaptic proteins in dopaminergic neurons; mice lacking Sept4 exhibit diminished dopaminergic neurotransmission due to scarcity of these presynaptic proteins. These data demonstrate an important role for septin scaffolds in the brain. In transgenic mice that express human alpha-synuclein(A53T) (a mutant protein responsible for familial PD), loss of Sept4 significantly enhances neuropathology and locomotor deterioration. In this PID model, insoluble deposits of Ser(129)-phosphorylated alpha-synuclein(A53T) are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects alpha-synuclein against self-aggregation and Ser(129) phosphorylation. Taken together, these data show that Sept4 may be involved in PID as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity.