MLKL deficiency alleviates neuroinflammation and motor deficits in the α-synuclein transgenic mouse model of Parkinson’s disease

作者：Lu Geng, Wenqing Gao, Hexige Saiyin, Yuanyuan Li, Yu Zeng, Zhifei Zhang, Zhifei Zhang, Zuolong Liu, Zuolong Liu, Qiang Gao, Ning Jiang, Ning Jiang, Xiaofei Yu, Xiangjun Chen, Suhua Li, Lei Chen, Aiqun Li, Aiqun Li, Yidong Shen, Yidong Shen, Haibing Zhang, Mei Tian, Zhuohua Zhang, Zhuohua Zhang, Jixi Li · 发表于：Molecular Neurodegeneration · 年份：2023 · DOI：10.1186/s13024-023-00686-5 · 被引用次数：56 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Nuclear Receptors and Signaling、Neuroinflammation and Neurodegeneration Mechanisms

Abstract 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 ...