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

Abstract

BackgroundPolyglutamine 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.MethodsGene 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.ResultsWe 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.ConclusionsOur 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.

Interferon mediated neuroinflammation in polyglutamine disease is not caused by RNA toxicity

“…We have previously shown that neuronal cells expressing toxic 59Q-TBP protein induce aberrant interferon signaling resulting in Stat1 mediated upregulation of interferon-stimulated genes (ISGs) 27 . In the tetracyclineinduced cell lines used in the study, we verified that STAT1 protein is induced and activated by phosphorylation ( Fig.…”

“…Moreover, we have shown that miR-29a/b targets VDAC1 as well as BACE1, preventing apoptosis in the neuronal cells 25 and ataxia in mice 26 . Recently, we showed that interferon signaling is elevated in this cellular model of SCA17, prompting the hypothesis that intercellular signaling leading to bystander cell death may aggravate the pathology of the disease 27 . Here, we explored the response of neuronal cells to CAG repeat RNA, specifically testing if CAG repeat RNA mediated toxicity was sufficient to explain the aberrant interferon signaling and cell death seen in polyQ expressing neuronal cells.…”

“…Our previous results showed that CAG repeat expansion in TATA-box binding protein leads to induction of interferon-stimulated genes and apoptosis 27 . Overcoming the limitations imposed by the constitutive expression of polyQ-TBP in our previous studies by doxycycline mediated induction of polyQ-TBP, we found that apoptosis preceded the formation of large protein aggregates.…”

The Emerging Role of microRNAs in Polyglutamine Diseases

“…SCA17 is caused by the expansion of a repeated Poly Q in the TBP gene and is characterized by intranuclear protein aggregation and selective loss of cerebellar neurons (Roshan et al, 2017). MiR-29a/b has been found down-regulation in a SCA17 cellular model by qRT PCR.…”

An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

“…1. It has been suggested that trinucleotide repeat expansion in the CAG in protein coding regions in the genome may cause polyglutamine (polyQ) disease, which induces a set of dominantly inherited neurodegenerative disorders including Huntington's disease (HD), spinocerebellar ataxia, type 1/2/3/6/7 (SCA-1/2/3/6/7), dentatorubropallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD) and spinobulbar muscularatrophy (8,9).…”