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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration
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Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration

机译:脑中核因子E2相关因子1的丧失导致蛋白酶体基因表达失调和神经退行性变

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摘要

The ubiquitin-proteasome pathway plays an important role in the pathogenesis of neurodegeneration, but mechanisms controlling expression of components in this pathway remain poorly understood. Nuclear factor E2-related factor 1 (Nrf 1) transcription factor has been shown to regulate expression of antioxidant and cyto-protective genes. To determine the function of Nrf1 in the brain, mice with a late-stage deletion of Nrf1 in neuronal cells were generated. Loss of Nrf1 leads to impaired proteasome function and neurodegeneration. Gene expression profiling and RT-PCR analysis revealed a coordinate down-regulation of various protea-somal genes including PsmB6, which encodes a catalytic subunit of the proteasome. Transcriptional analysis and chromatin immu-noprecipitation experiments demonstrated that PsmB6 is an Nrf1 target gene. These findings reveal Nrf1 as a key transcriptional regulator required for the expression of proteasomal genes in neurons and suggest that perturbations of Nrf 1 function may contribute to the pathogenesis of neurodegenerative diseases.
机译:泛素-蛋白酶体途径在神经变性的发病机理中起着重要作用,但是控制该途径中成分表达的机制仍然知之甚少。已显示核因子E2相关因子1(Nrf 1)转录因子可调节抗氧化剂和细胞保护性基因的表达。为了确定Nrf1在大脑中的功能,生成了在神经元细胞中具有Nrf1晚期缺失的小鼠。 Nrf1的丢失导致蛋白酶体功能受损和神经变性。基因表达谱分析和RT-PCR分析显示各种蛋白酶体基因包括PsmB6的协同下调,PsmB6编码蛋白酶体的催化亚基。转录分析和染色质免疫沉淀实验表明,PsmB6是Nrf1靶基因。这些发现揭示了Nrf1是在神经元中表达蛋白酶体基因所需的关键转录调节因子,并暗示Nrf 1功能的扰动可能有助于神经退行性疾病的发病。

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