Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Camino Ing. Ramón Padilla Sánchez #2100, Predio Las Agujas, Zapopan, Jalisco, México.
Mol Biol Rep. 2024 Sep 19;51(1):996. doi: 10.1007/s11033-024-09935-2.
The insoluble tangles of alpha-synuclein (α-syn) protein in the nigrostriatal circuit, characteristic of synucleinopathy, originate from low molecular weight oligomers, whose appearance and dissemination are related to neuroinflammation. These oligomeric forms of α-syn are considered highly cytotoxic but transient, so knowing the timing in which they appear remains challenging. Therefore, this study aimed to analyze the abundance of oligomeric forms of α-syn and tyrosine hydroxylase (TH) between 3 and 7 days after inducing neuroinflammation with lipopolysaccharide (LPS).
LPS (2.5 µg/2.5 µL) was stereotaxically injected in the substantia nigra (SN) of adult male Wistar rats, which were sacrificed 3, 5 and 7 days after this intervention. The brains were processed for semi quantitative Western blot, along with brains from control and sham animals. Our results show an increased expression of α-syn monomer (15 kDa) only 3 days after LPS infusion, and the formation of 50 KDa and 60 kDa α-syn oligomers in the SN and striatum (STR) between 3 and 7 days after LPS infusion. Furthermore, the presence of these oligomers was accompanied by a decrease in the expression of nigral TH.
These findings highlight the rapidity with which potentially toxic forms of α-syn appear in the nigrostriatal circuit after a neuroinflammatory challenge, in addition to allowing us to identify specific oligomers and a temporal relation with neurodegeneration of TH-positive cells. Knowledge of the timing and location in which these small oligomers appear is essential to developing therapeutic strategies to prevent its formation.
黑质纹状体回路中不溶性的α-突触核蛋白（α-syn）蛋白缠结是突触核蛋白病的特征，源自低分子量寡聚物，其出现和传播与神经炎症有关。这些α-syn 的寡聚形式被认为具有高度细胞毒性但短暂，因此了解它们出现的时间仍然具有挑战性。因此，本研究旨在分析脂多糖 (LPS) 诱导神经炎症后 3 至 7 天内寡聚形式的α-syn 和酪氨酸羟化酶 (TH) 的丰度。
将 LPS（2.5µg/2.5µL）立体定向注射到成年雄性 Wistar 大鼠的黑质 (SN) 中，在干预后 3、5 和 7 天处死这些大鼠。对大脑进行半定量 Western blot 处理，同时对对照和假手术动物的大脑进行处理。我们的结果显示，LPS 输注仅 3 天后，α-syn 单体（15 kDa）的表达增加，并且在 LPS 输注后 3 至 7 天，SN 和纹状体 (STR) 中形成 50 kDa 和 60 kDa 的 α-syn 寡聚物。此外，这些寡聚物的存在伴随着黑质 TH 表达的下降。
这些发现强调了在神经炎症挑战后，潜在毒性形式的α-syn 在黑质纹状体回路中迅速出现，此外还使我们能够识别特定的寡聚物及其与 TH 阳性细胞神经退行性变的时间关系。了解这些小寡聚物出现的时间和位置对于开发预防其形成的治疗策略至关重要。
