Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808-4124, USA.
J Neurosci Res. 2011 Sep;89(9):1471-7. doi: 10.1002/jnr.22677. Epub 2011 May 23.
Amino acid analogs promote translational errors that result in aberrant protein synthesis and have been used to understand the effects of protein misfolding in a variety of physiological and pathological settings. TDP-43 is a protein that is linked to protein aggregation and toxicity in a variety of neurodegenerative diseases. This study exposed primary rat neurons and astrocyte cultures to established amino acid analogs (canavanine and azetidine-2-carboxylic acid) and showed that both cell types undergo a dose-dependent increase in toxicity, with neurons exhibiting a greater degree of toxicity compared with astrocytes. Neurons and astrocytes exhibited similar increases in ubiquitinated and oxidized protein following analog treatment. Analog treatment increased heat shock protein (Hsp) levels in both neurons and astrocytes. In neurons, and to a lesser extent astrocytes, the levels of TDP-43 increased in response to analog treatment. Taken together, these data indicate that neurons exhibit preferential toxicity and alterations in TDP-43 in response to increased protein misfolding compared with astrocytes.
氨基酸类似物促进翻译错误，导致异常蛋白质合成，并已被用于在各种生理和病理环境中了解蛋白质错误折叠的影响。TDP-43 是一种与多种神经退行性疾病中的蛋白质聚集和毒性有关的蛋白质。本研究将原代大鼠神经元和星形胶质细胞培养物暴露于已建立的氨基酸类似物（瓜氨酸和氮杂环丁烷-2-羧酸）中，结果表明两种细胞类型均表现出剂量依赖性毒性增加，与星形胶质细胞相比，神经元表现出更高程度的毒性。类似物处理后，神经元和星形胶质细胞中的泛素化和氧化蛋白均增加。类似物处理增加了神经元和星形胶质细胞中的热休克蛋白 (Hsp) 水平。在神经元中，并且在较小程度上在星形胶质细胞中，TDP-43 的水平在响应类似物处理时增加。总之，这些数据表明，与星形胶质细胞相比，神经元对蛋白质错误折叠的反应表现出优先的毒性和 TDP-43 的改变。
