Synaptic phosphorylated α-synuclein in dementia with Lewy bodies
Synaptic phosphorylated α-synuclein in dementia with Lewy bodies
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DOI：
10.1093/brain/awx275
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发表时间：
2017-12-01
期刊：
影响因子：
14.5
通讯作者：
Lleo, Alberto
中科院分区：
文献类型：
--
作者：
Colom-Cadena, Marti;Pegueroles, Jordi;Lleo, Alberto
突触丧失发生在路易体痴呆（DLB）早期，但其与α -突触核蛋白病理的关系尚不清楚。通过阵列断层扫描显微镜，colam - cadena等人发现了DLB患者突触末端磷酸化的α -突触核蛋白小聚集体，支持α -突触核蛋白积累与突触功能障碍之间的直接关联。路易小体痴呆的特点是中枢神经系统中路易小体和路易神经突的积聚，两者主要由Ser129磷酸化的聚集的α -突触核蛋白组成。尽管磷酸化的α -突触核蛋白被认为在路易体痴呆和其他α -突触核蛋白病的突触中发挥毒性作用，但由于缺乏足够的光学显微镜分辨率来研究人类突触，难以获得精确突触定位的直接证据。在本研究中，我们应用阵列断层扫描技术，一种结合超薄组织切片和免疫荧光的显微技术，可以精确识别小结构，定量研究突触磷酸化α -突触核蛋白在路易小体痴呆中的病理。我们对5名路易体痴呆患者、5名阿尔茨海默病患者和5名健康对照者的大脑样本进行了阵列断层扫描，以分析突触磷酸化α -突触核蛋白免疫反应性的存在及其与突触大小的关系。主要分析是在路易体痴呆患者的扣带皮层和纹状体块中进行的。共分析了1 318 700个单突触前或突触后终末。我们发现磷酸化的α -突触核蛋白仅存在于路易小体痴呆病例中，可以以路易小体、路易神经突和小聚集体的形式识别（< 0.16 A μ m）(3)。19% - 25%的磷酸化α -突触核蛋白沉积主要以小聚集体的形式存在于突触前终末。与磷酸化α -突触核蛋白的小聚集体共定位的突触末端明显大于那些没有共定位的突触末端。最后，我们观察到突触中磷酸化的α -突触核蛋白聚集的梯度（pre - > pre + post - > postsynaptic）。这些结果表明，在路易体痴呆患者的突触前终末发现磷酸化的α -突触核蛋白，主要以磷酸化的α -突触核蛋白聚集体的形式存在，这些聚集体与突触形态的改变有关。总的来说，我们的数据支持病理性磷酸化的α -突触核蛋白可能破坏路易体痴呆中突触的结构和功能的观点。
Synaptic loss occurs early in dementia with Lewy bodies (DLB), but its relationship to alpha-synuclein pathology remains unclear. Using array tomography microscopy, Colom-Cadena et al. reveal small phosphorylated alpha-synuclein aggregates at synaptic terminals of DLB cases, supporting a direct association between alpha-synuclein accumulation and synaptic dysfunction.Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated alpha-synuclein phosphorylated at Ser129. Although phosphorylated alpha-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other alpha-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated alpha-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer's disease and five healthy control subjects to analyse the presence of phosphorylated alpha-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated alpha-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (< 0.16 A mu m(3)). Between 19% and 25% of phosphorylated alpha-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated alpha-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated alpha-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated alpha-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated alpha-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated alpha-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.