Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
Mol Cell Neurosci. 2018 Apr;88:249-257. doi: 10.1016/j.mcn.2018.02.011. Epub 2018 Feb 27.
The pro-apoptotic Bcl-2 homology 3 domain only (BH3-only) proteins are central regulators of cell death in various physiological and pathological conditions, including Alzheimer's disease (AD). Bcl-2 modifying factor (Bmf) is one such BH3-only protein that is implicated in various death paradigms such as anoikis, seizures, cancer and autoimmunity. It also co-operates with other BH3-only proteins such as Bim in various death paradigms. However, its role in neurodegeneration is under-investigated. Here, we report for the first time the essential role of Bmf and its co-operativity with direct activator BH3-only proteins Bim and Puma in neuron death induced by beta-amyloid (Aβ) toxicity or NGF deprivation. Oligomeric Aβ is main pathologic species in AD and NGF deprivation is relevant for both developmental as well as pathologic neuron death. We find that Bmf over-expression causes cell death and Bmf knockdown protects neurons against death evoked by Aβ or NGF deprivation. We also find that Bmf co-operates with other important BH3-only proteins such as Bim and Puma in neuron death induced by Aβ or NGF deprivation. Simultaneous knocking down of these molecules by their respective shRNAs provide enhanced protection against Aβ. Taken together, our results elucidate the essential role of Bmf and its co-operative effects with already known neuron death inducers, Bim and Puma, in neuron death evoked by Aβ treatment or NGF deprivation.
促凋亡 Bcl-2 同源结构域仅 3 （BH3-only）蛋白是各种生理和病理条件下细胞死亡的中央调节剂，包括阿尔茨海默病（AD）。Bcl-2 修饰因子（Bmf）是这样一种 BH3-only 蛋白，它涉及各种死亡模式，如失巢凋亡、癫痫发作、癌症和自身免疫。它还与其他 BH3-only 蛋白（如 Bim）在各种死亡模式中合作。然而，它在神经退行性变中的作用尚未得到充分研究。在这里，我们首次报道了 Bmf 的重要作用及其与直接激活 BH3-only 蛋白 Bim 和 Puma 在β-淀粉样蛋白（Aβ）毒性或 NGF 剥夺诱导的神经元死亡中的协同作用。寡聚 Aβ是 AD 的主要病理物质，NGF 剥夺与发育和病理神经元死亡都有关。我们发现 Bmf 过表达会导致细胞死亡，而 Bmf 敲低可保护神经元免受 Aβ或 NGF 剥夺引起的死亡。我们还发现 Bmf 与其他重要的 BH3-only 蛋白（如 Bim 和 Puma）在 Aβ或 NGF 剥夺诱导的神经元死亡中协同作用。通过各自的 shRNA 同时敲低这些分子可提供对 Aβ的增强保护。总之，我们的结果阐明了 Bmf 的重要作用及其与已知的神经元死亡诱导物 Bim 和 Puma 的协同作用，在 Aβ处理或 NGF 剥夺诱导的神经元死亡中。
