Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China.
State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
FASEB J. 2022 Sep;36(9):e22515. doi: 10.1096/fj.202200293R.
It has been shown that PP2A is critical for apoptosis in neural progenitor cells. However, it remains unknown whether PP2A is required for neuronal survival. To address this question, we generated forebrain-specific Ppp2cα knockout (KO) mice. We show that Ppp2cα KO mice display robust neuronal apoptosis and inflammatory responses in the postnatal cortex. Previous evidence has revealed that PD98059 is a potent ERK inhibitor and may protect the brain against cell death after cardiac arrest. To study whether PD98059 may have any effects on Ppp2cα KO mice, the latter was treated with this inhibitor. We demonstrated that the total number of cleaved caspase3 positive (+) cells in the cortex was significantly reduced in Ppp2cα KO mice treated with PD98059 compared with those without PD98059 treatment. We observed that the total number of IBA1+ cells in the cortex was significantly decreased in Ppp2cα KO mice treated with PD98059. Mechanistic analysis reveals that deletion of PP2Aca causes DNA damage, which may be attenuated by PD98059. Together, this study suggests that inhibition of ERK may be an effective strategy to reduce cell death in brain diseases with abnormal neuronal apoptosis.
已有研究表明，蛋白磷酸酶 2A（PP2A）对于神经祖细胞的凋亡至关重要。然而，PP2A 是否对于神经元的存活是必需的仍不清楚。为了解决这个问题，我们生成了大脑特异性 Ppp2cα 敲除（KO）小鼠。我们发现 Ppp2cα KO 小鼠在出生后皮层中表现出强烈的神经元凋亡和炎症反应。先前的证据表明 PD98059 是一种有效的 ERK 抑制剂，可能会保护心脏骤停后大脑免受细胞死亡的影响。为了研究 PD98059 是否对 Ppp2cα KO 小鼠有任何影响，我们用这种抑制剂对后者进行了处理。我们发现，与未用 PD98059 处理的 Ppp2cα KO 小鼠相比，用 PD98059 处理的 Ppp2cα KO 小鼠皮层中 cleaved caspase3 阳性（+）细胞的总数显著减少。我们观察到用 PD98059 处理的 Ppp2cα KO 小鼠皮层中 IBA1+细胞的总数显著减少。机制分析表明，PP2Aca 的缺失会导致 DNA 损伤，而 PD98059 可能会减轻这种损伤。总之，这项研究表明，抑制 ERK 可能是减少具有异常神经元凋亡的脑部疾病中细胞死亡的有效策略。
