Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration
Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration
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DOI：
10.1073/pnas.1019209108
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发表时间：
2011-05-17
影响因子：
11.1
通讯作者：
Chan, Jefferson Y.
中科院分区：
文献类型：
--
作者：
Lee, Candy S.;Lee, Chiashan;Chan, Jefferson Y.
泛素-蛋白酶体通路在神经退行性变的发病机制中起着重要的作用，但控制该通路中组分表达的机制仍然知之甚少。核因子E2相关因子1（Nrf 1）转录因子已被证明可以调节抗氧化和细胞保护基因的表达。为了确定Nrf 1在大脑中的功能，产生了神经元细胞中Nrf 1晚期缺失的小鼠。Nrf 1的缺失会导致蛋白酶体功能受损和神经退行性变。基因表达谱分析和RT-PCR分析揭示了各种蛋白酶体基因的协调下调，包括PsmB 6，其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证明PsmB 6是Nrf 1的靶基因。这些发现揭示了Nrf 1作为神经元中蛋白酶体基因表达所需的关键转录调节因子，并表明Nrf 1功能的扰动可能有助于神经退行性疾病的发病机制。
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 (Nrf1) transcription factor has been shown to regulate expression of antioxidant and cytoprotective 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 proteasomal genes including PsmB6, which encodes a catalytic subunit of the proteasome. Transcriptional analysis and chromatin immunoprecipitation 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 Nrf1 function may contribute to the pathogenesis of neurodegenerative diseases.