Parkinson’s disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. Currently, pharmacological interventions for PD remain inadequate. The cell necroptosis executor protein MLKL (Mixed-lineage kinase domain-like) is involved in various diseases, including inflammatory bowel disease and neurodegenerative diseases; however, its precise role in PD remains unclear. Here, we investigated the neuroprotective role of MLKL inhibition or ablation against primary neuronal cells and human iPSC-derived midbrain organoids induced by toxic α-Synuclein preformed fibrils (PFFs). Using a mouse model (Tg-Mlkl−/−) generated by crossbreeding the SNCA A53T synuclein transgenic mice with MLKL knockout (KO)mice, we assessed the impact of MLKL deficiency on the progression of Parkinsonian traits. Our findings demonstrate that Tg-Mlkl−/− mice exhibited a significant improvement in motor symptoms and reduced phosphorylated α-synuclein expression compared to the classic A53T transgenic mice. Furthermore, MLKL deficiency alleviated tyrosine hydroxylase (TH)-positive neuron loss and attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes. Single-cell RNA-seq (scRNA-seq) analysis of the SN of Tg-Mlkl−/− mice revealed a unique cell type-specific transcriptome profile, including downregulated prostaglandin D synthase (PTGDS) expression, indicating reduced microglial cells and dampened neuron death. Thus, MLKL represents a critical therapeutic target for reducing neuroinflammation and preventing motor deficits in PD.

中文翻译：

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MLKL 缺陷可减轻帕金森病 α-突触核蛋白转基因小鼠模型的神经炎症和运动缺陷

帕金森病 (PD) 是最具破坏性的神经退行性脑部疾病之一，其特征是黑质 (SN) 中多巴胺能神经元的逐渐丧失和 α-突触核蛋白聚集体的沉积。目前，针对帕金森病的药物干预措施仍然不足。细胞坏死性执行蛋白MLKL（混合谱系激酶结构域样）参与多种疾病，包括炎症性肠病和神经退行性疾病；然而，其在 PD 中的确切作用仍不清楚。在这里，我们研究了 MLKL 抑制或消融对由有毒 α-突触核蛋白预制原纤维 (PFF) 诱导的原代神经元细胞和人 iPSC 衍生的中脑类器官的神经保护作用。使用通过将 SNCA A53T 突触核蛋白转基因小鼠与 MLKL 敲除 (KO) 小鼠杂交产生的小鼠模型 (Tg-Mlkl−/−)，我们评估了 MLKL 缺陷对帕金森病特征进展的影响。我们的研究结果表明，与经典的 A53T 转基因小鼠相比，Tg-Mlkl−/− 小鼠的运动症状显着改善，磷酸化 α-突触核蛋白表达减少。此外，MLKL 缺乏通过抑制小胶质细胞和星形胶质细胞的激活，减轻了酪氨酸羟化酶 (TH) 阳性神经元的丢失并减轻了神经炎症。对 Tg-Mlkl−/− 小鼠 SN 的单细胞 RNA 序列 (scRNA-seq) 分析揭示了独特的细胞类型特异性转录组谱，包括下调的前列腺素 D 合酶 (PTGDS) 表达，表明小胶质细胞减少和神经元减弱死亡。因此，MLKL 代表了减少 PD 神经炎症和预防运动缺陷的关键治疗靶点。