microRNA dysregulation in polyglutamine toxicity of TATA-box binding protein is mediated through STAT1 in mouse neuronal cells

Background: 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. methods: 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. results: 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. conclusions: 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. © 2017 the author(s).