Kupershmidt Lana, Amit Tamar, Bar-Am Orit, Youdim Moussa B H, Blumenfeld Zeev
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel.
J Neurochem. 2007 Nov;103(3):962-71. doi: 10.1111/j.1471-4159.2007.04785.x. Epub 2007 Aug 6.
Activin is a member of the transforming growth factor-beta superfamily which comprises a growing list of multifunctional proteins that function as modulators of cell proliferation, differentiation, hormone secretion and neuronal survival. This study examined the neuroprotective effect of both Activin A and B in serum withdrawal and oxidative stress apoptotic cellular models and investigated the expression of pro- and anti-apoptotic proteins, which may account for the mechanism of Activin-induced neuroprotection. Here, we report that recombinant Activin A and B are neuroprotective against serum deprivation- and toxin- [either the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA) or the peroxynitrite donor, 3-(4-morpholinyl) sydnonimine hydrochloride (SIN-1)] induced neuronal death in human SH-SY5Y neuroblastoma cells. Furthermore, we demonstrate for the first time that transient transfection with Activin betaA or betaB significantly protect SH-SY5Y and rat pheochromocytoma PC12 cells against serum withdrawal-induced apoptosis. This survival effect is mediated by the Bcl-2 family members and involves inhibition of caspase-3 activation; reduction of cleaved poly-ADP ribose polymerase and phosphorylated H2A.X protein levels and elevation of tyrosine hydroxylase expression. These results indicate that both Activin-A and -B share the potential to induce neuroprotective activity and thus may have positive impact on aging and neurodegenerative diseases to retard the accelerated rate of neuronal degeneration.
激活素是转化生长因子-β超家族的成员之一，该超家族包含越来越多的多功能蛋白质，这些蛋白质作为细胞增殖、分化、激素分泌和神经元存活的调节剂发挥作用。本研究检测了激活素A和B在血清剥夺和氧化应激诱导的细胞凋亡模型中的神经保护作用，并研究了促凋亡蛋白和抗凋亡蛋白的表达，这可能解释激活素诱导神经保护的机制。在此，我们报告重组激活素A和B对血清剥夺和毒素[帕金森病诱导神经毒素6-羟基多巴胺(6-OHDA)或过氧亚硝酸盐供体盐酸3-(4-吗啉基)西多胺(SIN-1)]诱导的人SH-SY5Y神经母细胞瘤细胞神经元死亡具有神经保护作用。此外，我们首次证明用激活素βA或βB瞬时转染可显著保护SH-SY5Y和大鼠嗜铬细胞瘤PC12细胞免受血清剥夺诱导的凋亡。这种存活效应由Bcl-2家族成员介导，涉及抑制半胱天冬酶-3激活；降低裂解的聚ADP核糖聚合酶和磷酸化H2A.X蛋白水平，并提高酪氨酸羟化酶表达。这些结果表明，激活素A和B都具有诱导神经保护活性的潜力，因此可能对衰老和神经退行性疾病产生积极影响，以延缓神经元加速退变的速度。
