Lewy body dementias are characterized by deposition of alpha-synuclein (α-syn) protein aggregates known as Lewy bodies and Lewy neurites in cortical regions, in addition to brainstem. These aggregates are thought to cause the death of dopaminergic neurons in the substantia nigra and other vulnerable cell types in patients, leading to parkinsonism. There is evidence from mice that localized overexpression of wild-type α-syn leads to dopaminergic cell death in the substantia nigra. However, it is not known how cortical neurons are affected by α-syn. In this study, we used viral overexpression of α-syn to investigate whether localized overexpression within the cortex affects the density, length, and morphology of dendritic spines, which serve as a measure of synaptic connectivity. An AAV2/6 viral vector coding for wild-type human α-syn was used to target overexpression bilaterally to the medial prefrontal cortex within adult mice. After ten weeks the brain was stained using the Golgi-Cox method. Density of dendritic spines in the injected region was increased in layer V pyramidal neurons compared with animals injected with control virus. Immunohistochemistry in separate animals showed human α-syn expression throughout the region of interest, especially in presynaptic terminals. However, phosphorylated α-syn was seen in a discrete number of cells at the region of highest overexpression, localized mainly to the soma and nucleus. These findings demonstrate that at early timepoints, α-syn overexpression may alter connectivity in the cortex, which may be relevant to early stages of the disease. In addition, these findings contribute to the understanding of α-syn, which when overexpressed in the wildtype, non-aggregated state may promote spine formation. Loss of spines secondary to α-syn in cortex may require higher expression, longer incubation, cellular damage, concomitant dopaminergic dysfunction or other two-hit factors to lead to synaptic degeneration.

中文翻译：

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人类野生型 α-突触核蛋白的局部皮质过度表达导致小鼠树突棘密度增加。

路易体痴呆的特征在于，除了脑干外，皮质区域中还有称为路易体和路易神经突的 α-突触核蛋白 (α-syn) 蛋白质聚集体的沉积。这些聚集体被认为会导致患者黑质和其他脆弱细胞类型中的多巴胺能神经元死亡，从而导致帕金森综合征。有来自小鼠的证据表明，局部过度表达野生型 α-syn 会导致黑质中的多巴胺能细胞死亡。然而，目前尚不清楚 α-syn 如何影响皮质神经元。在这项研究中，我们使用 α-syn 的病毒过表达来研究皮层内的局部过表达是否影响树突棘的密度、长度和形态，这些都是衡量突触连接性的指标。使用编码野生型人 α-syn 的 AAV2/6 病毒载体将双侧过表达靶向成年小鼠的内侧前额叶皮层。十周后，使用 Golgi-Cox 方法对大脑进行染色。与注射对照病毒的动物相比，注射区域的树突棘密度在 V 层锥体神经元中增加。不同动物的免疫组织化学显示，整个目标区域，尤其是突触前末端，都有人类 α-syn 表达。然而，磷酸化的 α-syn 在高表达区域的离散数量的细胞中被观察到，主要位于胞体和细胞核。这些发现表明，在早期时间点，α-syn 过表达可能会改变皮层的连通性，这可能与疾病的早期阶段有关。此外，这些发现有助于理解 α-syn，当它在野生型中过表达时，非聚集状态可能会促进棘突形成。继发于皮质中 α-syn 的棘丢失可能需要更高的表达、更长的孵化时间、细胞损伤、伴随的多巴胺能功能障碍或其他双重打击因素，从而导致突触变性。