α-Synuclein (α-Syn) is a key pathogenic protein in α-synucleinopathies including Parkinson disease (PD) and Dementia with Lewy Bodies. The aggregation of α-Syn is believed to be deleterious and a critical step leading to neuronal dysfunction and death. One of the factors that may contribute to the initial steps of this aggregation is crosslinking through transglutaminase 2 (TG2). We previously demonstrated that overexpression of TG2 exacerbates α-Syn toxicity in mice and yeast by increasing the higher-order species of α-Syn. Herein, we investigated whether deletion of the TG2 encoding gene could mitigate the toxicity of α-Syn in vivo. Compared with α-Syn transgenic (Syn^Tg) mice, TG2 null /α-Syn transgenic mice (TG2^KO/Syn^Tg) exhibited a reduced amount of phosphorylated α-Syn aggregates and fewer proteinase K-resistant α-Syn aggregates in sections of brain tissue. Neuritic processes that are depleted in Syn^Tg mice compared to wild-type mice were preserved in double TG2^KO/Syn^Tg mice. Additionally, the neuroinflammatory reaction to α-Syn was attenuated in TG2^KO/Syn^Tg animals. These neuropathological markers of diminished α-Syn toxicity in the absence of TG2 were associated with better motor performance on the rotarod and balance beam. These results suggest that deleting TG2 reduces the toxicity of α-Syn in vivo and improves the behavioral performance of Syn^Tg mice. Accordingly, these findings collectively support pharmacological inhibition of TG2 as a potential disease modifying therapeutic strategy for α-synucleinopathies.

α-突触核蛋白 (α-Syn) 是 α-突触核蛋白病的关键致病蛋白，包括帕金森病 (PD) 和路易体痴呆。α-Syn 的聚集被认为是有害的，是导致神经元功能障碍和死亡的关键步骤。可能促成这种聚集的初始步骤的因素之一是通过转谷氨酰胺酶 2 (TG2) 进行交联。我们之前证明，TG2 的过表达通过增加 α-Syn 的高阶种类，加剧了小鼠和酵母中的 α-Syn 毒性。在此，我们研究了 TG2 编码基因的缺失是否可以减轻体内α-Syn 的毒性。与 α-Syn 转基因 (Syn ^Tg ) 小鼠相比，TG2 null /α-Syn 转基因小鼠 (TG2 ^KO /Syn ^Tg) 在脑组织切片中表现出减少的磷酸化 α-Syn 聚集体和较少的蛋白酶 K 抗性 α-Syn 聚集体。^{在双 TG2 KO} /Syn ^Tg小鼠中保留了与野生型小鼠相比在 Syn ^Tg小鼠中耗尽的神经炎过程。此外，在 TG2 ^KO /Syn ^Tg动物中，对 α-Syn 的神经炎症反应减弱。在没有 TG2 的情况下，这些减少 α-Syn 毒性的神经病理学标志物与更好的旋转杆和平衡木运动性能相关。这些结果表明，删除 TG2 可降低体内α-Syn 的毒性并改善 Syn ^{Tg的行为表现}老鼠。因此，这些发现共同支持 TG2 的药理学抑制作为 α-突触核蛋白病的潜在疾病修饰治疗策略。