Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi District, Zhengzhou 450052, China; Henan Medical College of Zhengzhou University, No.50 Zhongyuan Road, Erqi District, Zhengzhou 450052, China.
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi District, Zhengzhou 450052, China; Henan Medical College of Zhengzhou University, No.50 Zhongyuan Road, Erqi District, Zhengzhou 450052, China; Department of Neurological Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi District, Zhengzhou 450052, China.
Neurosci Lett. 2022 Sep 25;788:136862. doi: 10.1016/j.neulet.2022.136862. Epub 2022 Sep 6.
Ceramides, the key component of sphingolipid metabolism and second messengers, have been associated with neurodegenerative diseases progression and pathology, and can induce neuronal apoptosis and necrosis, but the effect of ceramide on parthanatos has not been fully elucidated. In this study, we investigated the ceramide-mediated parthanatos pathway and the role of macrophage inhibitory factor (MIF) in parthanatos. We found that ceramide significantly diminished the viability and induced the death of primary cortical neurons. These effects were not prevented by treatment with the pan-caspase inhibitor Z-VAD-FMK treatment; in contrast, treatment with the poly (ADP ribosyl) polymerase-1 (PARP-1) inhibitor ABT-888 prevented these ceramide-mediated effects. Specifically, ceramide induced PARP-1 overactivation, increased PAR polymer levels, facilitated apoptosis-inducing factor (AIF) and MIF nuclear translocation and induced DNA damage. Knockdown of MIF with an adenovirus carrying a MIF short hairpin RNA (shRNA) inhibited ceramide-induced DNA damage and neuronal death, but nuclear translocation of AIF was unaffected. Furthermore, ceramide increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) significantly inhibited PAR production and neuronal death. These findings suggested that ceramide induced neuronal parthanatos by increasing ROS levels and that MIF might be downstream of AIF in the ceramide-mediated parthanatos pathway. In conclusion, our results suggest that knocking down MIF expression may be a potential therapeutic strategy for nervous system diseases.
神经酰胺是神经退行性疾病进展和病理的关键组成部分，也是鞘脂代谢和第二信使，可诱导神经元凋亡和坏死，但神经酰胺对细胞坏死性凋亡的影响尚未完全阐明。在这项研究中，我们研究了神经酰胺介导的细胞坏死性凋亡途径以及巨噬细胞抑制因子（MIF）在细胞坏死性凋亡中的作用。我们发现神经酰胺显著降低原代皮质神经元的活力并诱导其死亡。这些作用不能通过使用泛半胱天冬酶抑制剂 Z-VAD-FMK 来预防；相反，使用多聚（ADP 核糖）聚合酶-1（PARP-1）抑制剂 ABT-888 可预防这些神经酰胺介导的作用。具体而言，神经酰胺诱导 PARP-1 过度激活，增加 PAR 聚合物水平，促进凋亡诱导因子（AIF）和 MIF 核易位，并诱导 DNA 损伤。用携带 MIF 短发夹 RNA（shRNA）的腺病毒敲低 MIF 可抑制神经酰胺诱导的 DNA 损伤和神经元死亡，但 AIF 的核易位不受影响。此外，神经酰胺增加活性氧（ROS）水平，N-乙酰半胱氨酸（NAC）显著抑制 PAR 产生和神经元死亡。这些发现表明，神经酰胺通过增加 ROS 水平诱导神经元细胞坏死性凋亡，并且 MIF 可能是神经酰胺介导的细胞坏死性凋亡途径中 AIF 的下游分子。总之，我们的结果表明，敲低 MIF 表达可能是神经系统疾病的一种潜在治疗策略。
