While the initial pathology of Parkinson’s disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid.

中文翻译：

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LAG3 在人类和小鼠神经元中不表达，并且不调节 α-突触核蛋白病

虽然帕金森病和其他 α-突触核蛋白病的最初病理通常局限于有限的大脑区域，但它可以扩散并逐渐影响邻近和远处的大脑区域。这一过程可能由 α-突触核蛋白原纤维的细胞受体控制，其中之一被认为是 LAG3 免疫检查点分子。在这里，我们分析了 LAG3 在人类和小鼠大脑中的表达模式。使用各种方法和模型系统，我们没有发现神经元表达 LAG3 的证据。虽然我们证实 LAG3 与 α-突触核蛋白原纤维相互作用，但这种相互作用的特异性似乎有限。此外，在培养的人神经细胞中过度表达 LAG3 不会导致离体α-突触核蛋白病理学恶化。A53T α-突触核蛋白转基因小鼠的总体存活率不受 LAG3 耗竭的影响，并且海马切片培养物中 α-突触核蛋白损伤的种子诱导也不受 LAG3 敲除的影响。这些数据表明，所提出的 LAG3 在 α-突触核蛋白病传播中的作用并不普遍有效。