Department of Chemistry, University of Texas at El Paso, El Paso, TX 79968, USA.
Biochem Biophys Res Commun. 2012 Sep 28;426(3):438-44. doi: 10.1016/j.bbrc.2012.08.121. Epub 2012 Sep 4.
Mitochondrial dysfunction, leading to elevated levels of reactive oxygen species, is associated with the pathogenesis of neurodegenerative disorders. Rotenone, a mitochondrial stressor induces caspase-9 and caspase-3 activation leading proteolytic cleavage of substrate nuclear poly(ADP-ribose) polymerase (PARP). PARP cleavage is directly related to apoptotic cell death. In this study, we have monitored the aggregation of green-fluorescent protein (GFP)-tagged synphilin-1, as a rotenone-induced Parkinsonia-onset biomarker. We report that the innate ketone body, Na-D-β-hydroxybutyrate (NaβHB) reduces markedly the incidence of synphilin-1 aggregation. Furthermore, our data reveal that the metabolic byproduct also prevents rotenone-induced caspase-activated apoptotic cell death in dopaminergic SH-SY5Y cells. Together, these results suggest that NaβHB is neuroprotective; it attenuates effects originating from mitochondrial insult and can serve as a scaffold for the design and development of sporadic neuropathies.
线粒体功能障碍导致活性氧水平升高，与神经退行性疾病的发病机制有关。鱼藤酮是一种线粒体应激物，可诱导半胱天冬酶-9 和半胱天冬酶-3 的激活，导致底物核多聚（ADP-核糖）聚合酶（PARP）的蛋白水解切割。PARP 切割与细胞凋亡直接相关。在这项研究中，我们监测了绿色荧光蛋白（GFP）标记的 synphilin-1 的聚集，作为鱼藤酮诱导帕金森病发病的生物标志物。我们报告说，内源性酮体 Na-D-β-羟基丁酸（NaβHB）显著降低 synphilin-1 聚集的发生率。此外，我们的数据还揭示了该代谢副产物还可以防止多巴胺能 SH-SY5Y 细胞中鱼藤酮诱导的半胱天冬酶激活的细胞凋亡。总之，这些结果表明 NaβHB 具有神经保护作用；它可以减轻源自线粒体损伤的影响，并可作为设计和开发散发性神经病变的支架。
