Pathological examination of dementia with Lewy bodies patients identified the presence of abnormal α-synuclein (αSyn) aggregates in the presynaptic terminals. αSyn is involved in the regulation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Importantly, αSyn-transgenic mouse and postmortem examination of patients with Parkinson's disease have demonstrated the abnormal distribution of SNARE protein in presynaptic terminals. In this study, we investigated the effects of SNARE dysfunction on endogenous αSyn using Snap25(S187A/S187A) mutant mice. These mice have homozygous knock-in gene encoding unphosphorylatable S187A-substituted synaptosomal-associated protein of 25 kDa (SNAP-25). The mice displayed a significant age-dependent change in the distribution of αSyn and its Ser(129)-phosphorylated form in abnormally hypertrophied glutamatergic nerve terminals in the striatum. Electron-microscopic analysis revealed the abnormally condensed synaptic vesicles with concomitant mislocalization of αSyn protein to the periactive zone in the glutamatergic nerve terminals. However, the Snap25(S187A/S187A) mutant mouse harbored no abnormalities in the nigrostriatal dopaminergic neurons. Our present results suggest that SNARE dysfunction is the initial trigger of mislocalization and accumulation of αSyn, and probably is an important pathomechanism of α-synucleinopathies.

译文

:对路易体痴呆患者的病理检查发现突触前末梢存在异常的α-突触核蛋白(αSyn)聚集体。 αSyn参与可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体(SNARE)复合物的调节。重要的是,对帕金森氏病患者进行αSyn转基因小鼠和死后检查已证明,SNARE蛋白在突触前末端异常分布。在这项研究中,我们调查了Snapare功能障碍对使用Snap25(S187A / S187A)突变小鼠的内源性αSyn的影响。这些小鼠具有编码25kDa的不可磷酸化的S187A-取代的突触体相关蛋白的纯合敲入基因(SNAP-25)。小鼠在纹状体中异常肥大的谷氨酸能神经末梢中显示αSyn及其Ser(129)-磷酸化形式的分布具有明显的年龄依赖性。电子显微镜分析显示,异常浓缩的突触囊泡伴有αSyn蛋白向谷氨酸能神经末梢的活动区误定位。但是,Snap25(S187A / S187A)突变小鼠的黑质纹状体多巴胺能神经元中没有异常。我们目前的研究结果表明,SNARE功能障碍是αSyn错位和积累的最初诱因,并且可能是α-突触核蛋白病的重要发病机制。

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