Favit A, Grimaldi M, Alkon D L
Laboratory of Adaptive Systems, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20817, USA.
J Neurochem. 2000 Sep;75(3):1258-63. doi: 10.1046/j.1471-4159.2000.0751258.x.
In many neurodegenerative disorders, such as Alzheimer's disease, inclusions containing ubiquitinated proteins have been found in the brain, suggesting a pathophysiological role for ubiquitin-mediated proteasomal degradation of neuronal proteins. Here we show for the first time that the beta-amyloid fragment 1-40, which in micromolar levels causes the death of cortical neurons, also induces the ubiquitination of several neuronal proteins. Prevention of ubiquitination and inhibition of proteasome activity block the neurotoxic effect of beta-amyloid. These data suggest that beta-amyloid neurotoxicity may cause toxicity through the activation of protein degradation via the ubiquitin-proteasome pathway. These findings suggest possible new pharmacological targets for the prophylaxis and/or treatment of Alzheimer's disease and possibly for other related neurodegenerative disorders.
在许多神经退行性疾病中，如阿尔茨海默病，大脑中已发现含有泛素化蛋白的包涵体，这表明泛素介导的神经元蛋白蛋白酶体降解具有病理生理作用。在此我们首次表明，微摩尔水平的β-淀粉样蛋白片段1-40可导致皮质神经元死亡，还可诱导多种神经元蛋白的泛素化。泛素化的预防和蛋白酶体活性的抑制可阻断β-淀粉样蛋白的神经毒性作用。这些数据表明，β-淀粉样蛋白神经毒性可能通过泛素-蛋白酶体途径激活蛋白质降解而导致毒性。这些发现提示了预防和/或治疗阿尔茨海默病以及可能其他相关神经退行性疾病的新的药理学靶点。
