Roshan Reema, Choudhary Ashwani, Bhambri Aksheev, Bakshi Bhawani, Ghosh Tanay, Pillai Beena
CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India.
Indian Institute of Science, Centre for Neuroscience, Bangalore, 560012, Karnataka, India.
J Neuroinflammation. 2017 Aug 3;14(1):155. doi: 10.1186/s12974-017-0925-3.
Polyglutamine diseases constitute a class of neurodegenerative disorders associated with expansion of the cytosine-adenine-guanine (CAG) triplet, in protein coding genes. Expansion of a polyglutamine tract in the N-terminal of TBP is the causal mutation in SCA17. Brain sections of patients with spinocerebellar ataxia 17 (SCA17), a type of neurodegenerative disease, have been reported to contain protein aggregates of TATA-binding protein (TBP). It is also implicated in other neurodegenerative diseases like Huntington's disease, since the protein aggregates formed in such diseases also contain TBP. Dysregulation of miR-29a/b is another common feature of neurodegenerative diseases including Alzheimer's disease, Huntington's disease, and SCA17. Using a cellular model of SCA17, we identified key connections in the molecular pathway from protein aggregation to miRNA dysregulation.
Gene expression profiling was performed subsequent to the expression of TBP containing polyglutamine in a cellular model of SCA17. We studied the expression of STAT1 and other interferon-gamma dependent genes in neuronal apoptosis. The molecular pathway leading to the dysregulation of miRNA in response of protein aggregation and interferon release was investigated using RNAi-mediated knockdown of STAT1.
We show that the accumulation of polyglutamine-TBP in the cells results in interferon-gamma release which in turn signals through STAT1 leading to downregulation of miR-29a/b. We propose that the release of interferons by cells harboring toxic protein aggregates may trigger a bystander effect resulting in loss of neurons. Interferon-gamma also led to upregulation of miR-322 although this effect is not mediated through STAT1.
Our investigation shows that neuroinflammation could be an important player in mediating the transcriptional dysregulation of miRNA and the subsequent apoptotic effect of toxic polyglutamine-TBP. The involvement of immunomodulators in polyglutamine diseases holds special therapeutic relevance in the light of recent findings that interferon-gamma can modulate behavior.
多聚谷氨酰胺疾病是一类与蛋白质编码基因中胞嘧啶 - 腺嘌呤 - 鸟嘌呤（CAG）三联体扩增相关的神经退行性疾病。TBP N端多聚谷氨酰胺序列的扩增是脊髓小脑共济失调17型（SCA17）的致病突变。据报道，神经退行性疾病脊髓小脑共济失调17型（SCA17）患者的脑切片中含有TATA结合蛋白（TBP）的蛋白聚集体。它也与其他神经退行性疾病如亨廷顿舞蹈病有关，因为在这些疾病中形成的蛋白聚集体也含有TBP。miR - 29a/b失调是包括阿尔茨海默病、亨廷顿舞蹈病和SCA17在内的神经退行性疾病的另一个共同特征。利用SCA17细胞模型，我们确定了从蛋白质聚集到miRNA失调的分子途径中的关键联系。
在SCA17细胞模型中表达含多聚谷氨酰胺的TBP后进行基因表达谱分析。我们研究了神经元凋亡中STAT1和其他干扰素 - γ依赖基因的表达。使用RNAi介导的STAT1敲低研究了导致蛋白质聚集和干扰素释放时miRNA失调的分子途径。
我们发现细胞中多聚谷氨酰胺 - TBP的积累导致干扰素 - γ释放，进而通过STAT1发出信号，导致miR - 29a/b下调。我们提出，含有有毒蛋白聚集体的细胞释放干扰素可能引发旁观者效应，导致神经元丢失。干扰素 - γ也导致miR - 322上调，尽管这种效应不是通过STAT1介导的。
我们的研究表明，神经炎症可能是介导miRNA转录失调以及有毒多聚谷氨酰胺 - TBP随后凋亡效应的重要因素。鉴于最近发现干扰素 - γ可以调节行为，免疫调节剂在多聚谷氨酰胺疾病中的作用具有特殊的治疗意义。
