Seeding and transgenic overexpression of alpha-synuclein triggers dendritic spine pathology in the neocortex.
Seeding and transgenic overexpression of alpha-synuclein triggers dendritic spine pathology in the neocortex.
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α-突触核蛋白的播种和转基因过表达触发了新皮层中的树突棘病理学。
DOI：
10.15252/emmm.201607305
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发表时间：
2017-05
影响因子：
11.1
通讯作者：
Herms J
中科院分区：
文献类型：
--
作者：
Blumenstock S;Rodrigues EF;Peters F;Blazquez-Llorca L;Schmidt F;Giese A;Herms J
尽管错误折叠和聚集的α -突触核蛋白（α - syn）在突触核蛋白病的疾病进展中得到了认可，但其在皮层回路损伤和突触可塑性中的作用仍不完全清楚。我们使用两种不同的方法研究了α -突触核蛋白积累如何影响小鼠体感觉皮层的突触可塑性。对过表达野生型人α -突触核蛋白的小鼠进行了根尖树突的长期体内成像。此外，通过颅内注射预先形成的α -突触核蛋白原纤维来诱导皮质α -突触病理。我们发现过表达α -突触核蛋白的小鼠表现出脊柱密度降低和脊柱动力学异常，并以年龄依赖的方式存在。我们还提供了种子α‐突触核蛋白聚集体对树突结构有害影响的证据。我们观察到V层锥体神经元的脊柱丢失和树突轴的营养不良变形。我们的研究结果提供了与突触核蛋白病相关的痴呆的病理生理学联系，并可能对体内树突脊柱病理的潜在候选药物进行评估。
Although misfolded and aggregated α‐synuclein (α‐syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how α‐synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct approaches. Long‐term in vivo imaging of apical dendrites was performed in mice overexpressing wild‐type human α‐synuclein. Additionally, intracranial injection of preformed α‐synuclein fibrils was performed to induce cortical α‐syn pathology. We find that α‐synuclein overexpressing mice show decreased spine density and abnormalities in spine dynamics in an age‐dependent manner. We also provide evidence for the detrimental effects of seeded α‐synuclein aggregates on dendritic architecture. We observed spine loss as well as dystrophic deformation of dendritic shafts in layer V pyramidal neurons. Our results provide a link to the pathophysiology underlying dementia associated with synucleinopathies and may enable the evaluation of potential drug candidates on dendritic spine pathology in vivo.