Increasing evidence has shown that mitochondrial dysfunction and iron accumulation contribute to the pathogenesis of Parkinson's disease (PD). Nedd4 family interacting protein 1 (Ndfip1) is an adaptor protein of the Nedd4 E3 ubiquitin ligases. We have previously reported that Ndfip1 showed a neuroprotective effect in cell models of PD. However, whether Ndfip1 could protect dopaminergic neurons in PD animal models in vivo and the possible mechanisms are not known. Here, our results showed that the expression of Ndfip1 decreased in the substantia nigra (SN) of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mouse model. Overexpression of Ndfip1 could improve MPTP-induced motor dysfunction significantly and antagonize the loss of dopaminergic neurons in the SN of MPTP-induced mice. Further study showed that overexpression of Ndfip1 might protect against MPTP-induced neurotoxicity through regulation of voltage-dependent anion-selective channel (VDAC). In addition, we observed the downregulation of Ndfip1 and upregulation of VDAC1/2 in 1-methyl-4-phenylpyridinium ion (MPP)-induced SH-SY5Y cells. Furthermore, high expression of Ndfip1 in SH-SY5Y cells inhibited MPP-induced increase of VDAC1/2 and restored MPP-induced mitochondrial dysfunction. Furthermore, Ndfip1 prevented MPP-induced increase in the expression of long-chain acyl-CoA synthetase 4 (ACSL4), suggesting the possible role of Ndfip1 in regulating ferroptosis. Our results provide new evidence for the neuroprotective effect of Ndfip1 on dopaminergic neurons in PD animal models and provide promising targets for the treatment of iron-related diseases, including PD.

中文翻译：

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Ndfip1 通过调节帕金森病线粒体功能和铁死亡来保护多巴胺能神经元

越来越多的证据表明，线粒体功能障碍和铁积累会导致帕金森病 (PD) 的发病机制。 Nedd4 家族相互作用蛋白 1 (Ndfip1) 是 Nedd4 E3 泛素连接酶的接头蛋白。我们之前报道过 Ndfip1 在 PD 细胞模型中显示出神经保护作用。然而，Ndfip1是否能够在体内保护PD动物模型中的多巴胺能神经元以及可能的机制尚不清楚。在这里，我们的结果表明，1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型的黑质（SN）中Ndfip1的表达下降。 Ndfip1的过表达可以显着改善MPTP诱导的运动功能障碍，并拮抗MPTP诱导的小鼠SN中多巴胺能神经元的损失。进一步的研究表明，Ndfip1 的过度表达可能通过调节电压依赖性阴离子选择性通道 (VDAC) 来防止 MPTP 诱导的神经毒性。此外，我们观察到 1-甲基-4-苯基吡啶鎓离子 (MPP) 诱导的 SH-SY5Y 细胞中 Ndfip1 下调和 VDAC1/2 上调。此外，SH-SY5Y细胞中Ndfip1的高表达抑制了MPP诱导的VDAC1/2的增加并恢复了MPP诱导的线粒体功能障碍。此外，Ndfip1 阻止 MPP 诱导的长链酰基辅酶 A 合成酶 4 (ACSL4) 表达增加，表明 Ndfip1 在调节铁死亡中可能发挥作用。我们的研究结果为 Ndfip1 对 PD 动物模型中多巴胺能神经元的神经保护作用提供了新的证据，并为治疗包括 PD 在内的铁相关疾病提供了有前景的靶点。