Li Taole, Liu Jiabin, Huang Xiurong, Xie Yixuan, Hu Yuxuan, Xu Qian, Tang Beisha, Tan Jieqiong, Guo Jifeng
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Mol Neurobiol. 2025 Jul 28. doi: 10.1007/s12035-025-05257-x.
Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by the progressive loss of dopaminergic neurons. Mutations in the PLA2G6 gene, which encodes calcium-independent phospholipase A2 (iPLA2β), have been associated with autosomal recessive early-onset parkinsonism, a subtype of neurodegeneration marked by brain iron accumulation. Although the pathogenic mechanisms underlying PLA2G6-related neurodegeneration remains unclear, disturbances in iron metabolism, neuroinflammation, and mitochondrial dysfunction are thought to play key roles. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently been implicated in PD. Here, we demonstrate that the iPLA2β deficiency in dopaminergic neurons induces ferroptosis, aggravating neurodegeneration and motor deficits in a mouse model of PLA2G6-associated neurodegeneration (PLAN). This ferroptotic phenotype is characterized by increased iron accumulation, elevated lipid peroxidation, and impaired antioxidant defenses, including downregulation of ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4). We further identify peroxiredoxin 6 (PRDX6) as a direct binding partner of iPLA2β and a critical regulator of ferroptosis. Loss of iPLA2β destabilizes PRDX6, promoting its degradation and thereby enhancing ferroptotic susceptibility. Notably, restoration of PRDX6 expression alleviates ferroptosis in iPLA2β-deficient cells, highlighting the protective role for the PRDX6/FTH1/GPX4 axis in maintaining redox homeostasis. Furthermore, treatment with the ferroptosis inhibitor Liproxstatin-1 (Lip-1) attenuated motor dysfunction and dopaminergic neuron loss in PLA2G6 knockout (KO) mice. Collectively, our findings uncover a novel mechanism linking iPLA2β deficiency to ferroptosis in PD and suggest ferroptosis inhibition as a promising therapeutic strategy for PD patients with PLA2G6 mutations.
帕金森病（PD）是一种进行性神经退行性疾病，主要特征是多巴胺能神经元逐渐丧失。编码钙非依赖性磷脂酶A2（iPLA2β）的PLA2G6基因突变与常染色体隐性早发性帕金森综合征有关，后者是一种以脑铁蓄积为特征的神经退行性疾病亚型。尽管PLA2G6相关神经退行性变的致病机制尚不清楚，但铁代谢紊乱、神经炎症和线粒体功能障碍被认为起关键作用。铁死亡是一种由脂质过氧化驱动的铁依赖性调节性细胞死亡形式，最近被认为与帕金森病有关。在此，我们证明多巴胺能神经元中的iPLA2β缺陷会诱导铁死亡，加重PLA2G6相关神经退行性变（PLAN）小鼠模型中的神经退行性变和运动缺陷。这种铁死亡表型的特征是铁蓄积增加、脂质过氧化升高以及抗氧化防御受损，包括铁蛋白重链1（FTH1）和谷胱甘肽过氧化物酶4（GPX4）的下调。我们进一步确定过氧化物酶体增殖物激活受体6（PRDX6）是iPLA2β的直接结合伴侣和铁死亡的关键调节因子。iPLA2β的缺失使PRDX6不稳定，促进其降解，从而增强铁死亡易感性。值得注意的是，恢复PRDX6表达可减轻iPLA2β缺陷细胞中的铁死亡，突出了PRDX6/FTH1/GPX4轴在维持氧化还原稳态中的保护作用。此外，用铁死亡抑制剂Liproxstatin-1（Lip-1）治疗可减轻PLA2G6基因敲除（KO）小鼠的运动功能障碍和多巴胺能神经元损失。总的来说，我们的研究结果揭示了一种将iPLA2β缺陷与帕金森病中铁死亡联系起来的新机制，并表明抑制铁死亡是治疗PLA2G6突变帕金森病患者的一种有前景的治疗策略。
