Visualization of early oligomeric α-synuclein pathology and its impact on the dopaminergic system in the (Thy-1)-h[A30P]α-syn transgenic mouse model,Journal of Neuroscience Research

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Visualization of early oligomeric α-synuclein pathology and its impact on the dopaminergic system in the (Thy-1)-h[A30P]α-syn transgenic mouse model
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2021-07-22 , DOI: 10.1002/jnr.24927
Anish Behere ₁ , Per-Ove Thörnqvist ₂ , Svante Winberg ₂ , Martin Ingelsson ₁ , Joakim Bergström ₁ , Sara Ekmark-Lewén ₁

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Aggregation of alpha-synuclein (α-syn) into Lewy bodies and Lewy neurites is a pathological hallmark in the Parkinson´s disease (PD) brain. The formation of α-syn oligomers is believed to be an early pathogenic event and the A30P mutation in the gene encoding α-syn, causing familial PD, has been shown to cause an accelerated oligomerization. Due to the problem of preserving antigen conformation on tissue surfaces, α-syn oligomers are difficult to detect ex vivo using conventional immunohistochemistry with oligomer-selective antibodies. Herein, we have instead employed the previously reported α-syn oligomer proximity ligation assay (ASO-PLA), along with a wide variety of biochemical assays, to discern the pathological progression of α-syn oligomers and their impact on the dopaminergic system in male and female (Thy-1)-h[A30P]α-syn transgenic (A30P-tg) mice. Our results reveal a previously undetected abundance of α-syn oligomers in midbrain of young mice, whereas phosphorylated (pS129) and proteinase k-resistant α-syn species were observed to a larger extent in aged mice. Although we did not detect loss of dopaminergic neurons in A30P-tg mice, a dysregulation in the monoaminergic system was recorded in older mice. Taken together, ASO-PLA should be a useful method for the detection of early changes in α-syn aggregation on brain tissue, from experimental mouse models in addition to post mortem PD cases.

中文翻译：

(Thy-1)-h[A30P]α-syn 转基因小鼠模型中早期寡聚 α-突触核蛋白病理学及其对多巴胺能系统的影响的可视化

α-突触核蛋白 (α-syn) 聚集成路易体和路易神经突是帕金森病 (PD) 大脑的病理标志。α-syn 寡聚体的形成被认为是早期致病事件，编码 α-syn 的基因中的 A30P 突变导致家族性 PD，已被证明会导致寡聚化加速。由于在组织表面保留抗原构象的问题，α-syn 寡聚体难以离体检测使用具有寡聚体选择性抗体的常规免疫组织化学。在这里，我们改为采用先前报道的 α-syn 寡聚体邻近连接测定 (ASO-PLA) 以及各种生化测定来辨别 α-syn 寡聚体的病理进展及其对男性多巴胺能系统的影响和雌性 (Thy-1)-h[A30P]α-syn 转基因 (A30P-tg) 小鼠。我们的结果揭示了年轻小鼠中脑中先前未检测到的丰富的 α-syn 寡聚体，而在老年小鼠中更大程度地观察到磷酸化（pS129）和蛋白酶 k 抗性 α-syn 物种。虽然我们没有在 A30P-tg 小鼠中检测到多巴胺能神经元的损失，但在老年小鼠中记录到单胺能系统的失调。综合起来，验尸PD 病例。

更新日期：2021-07-22

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