Ding Qunxing, Dimayuga Edgardo, Markesbery William R, Keller Jeffrey N
205 Sanders-Brown Center on Aging, 800 S. Limestone, University of Kentucky, Lexington, Kentucky 40536-0230, USA.
FASEB J. 2006 Jun;20(8):1055-63. doi: 10.1096/fj.05-5495com.
Proteasome inhibition occurs during normal aging and in a variety of age-related diseases, with inhibition of proteasome function sufficient to induce physiological and pathological alterations observed in each of these conditions. It is presumed that proteasome inhibition induces cellular alterations by promoting rapid protein accumulation, as the direct result of impairments in protein removal, which assumes protein synthesis remains relatively unchanged during proteasome inhibition. We conducted experimentation using established proteasome inhibitors and primary rat neuron cultures in order to elucidate whether proteasome inhibition had any effect on neuronal protein synthesis. Proteasome inhibition impaired neuronal protein synthesis, with concentrations of inhibitor necessary to significantly inhibit protein synthesis similar to the concentrations necessary to induce subsequent neuron death. The inhibition of protein synthesis was reversible during the first 6 h of treatment, with the neurotoxicity of proteasome inhibition reversible during the first 12 h of treatment. These studies are the first to demonstrate a potentially important interplay between the proteasome and protein synthesis in neurons, and the first to identify that some effects of proteasome inhibition are reversible in neurons. Together these findings have important implications for understanding proteasome inhibition as a potential contributor to aging and age-related disease.
蛋白酶体抑制在正常衰老过程以及多种与年龄相关的疾病中都会发生，蛋白酶体功能的抑制足以诱发在这些情况下所观察到的生理和病理改变。据推测，蛋白酶体抑制通过促进蛋白质快速积累来诱导细胞改变，这是蛋白质清除受损的直接结果，该过程假定在蛋白酶体抑制期间蛋白质合成保持相对不变。我们使用已有的蛋白酶体抑制剂和原代大鼠神经元培养物进行实验，以阐明蛋白酶体抑制是否对神经元蛋白质合成有任何影响。蛋白酶体抑制损害了神经元蛋白质合成，显著抑制蛋白质合成所需的抑制剂浓度与诱导随后神经元死亡所需的浓度相似。在治疗的前6小时内，蛋白质合成的抑制是可逆的，在治疗的前12小时内，蛋白酶体抑制的神经毒性是可逆的。这些研究首次证明了蛋白酶体与神经元中蛋白质合成之间潜在的重要相互作用，并且首次确定蛋白酶体抑制的某些作用在神经元中是可逆的。这些发现共同对于理解蛋白酶体抑制作为衰老和与年龄相关疾病的潜在促成因素具有重要意义。
