Abstract
Polyglutamine diseases are neurodegenerative diseases that occur due to the expansion of CAG repeat regions in coding sequences of genes. Previously, we have shown the formation of large protein aggregates along with activation of the interferon pathway leading to apoptosis in a cellular model of SCA17. Here, we corroborate our previous results in a tetracycline-inducible model of SCA17. Interferon gamma and lambda were upregulated in 59Q-TBP expressing cells as compared to 16Q-TBP expressing cells. Besides interferon-stimulated genes, the SCA17 model and Huntington’s mice brain samples showed upregulation of RNA sensors. However, in this improved model interferon pathway activation and apoptosis preceded the formation of large polyglutamine aggregates, suggesting a role for CAG repeat RNA or soluble protein aggregates. A polyglutamine minus mutant of TBP, expressing polyCAG mRNA, was created by site directed mutagenesis of 10 potential start codons. Neither this long CAG embedded mRNA nor short polyCAG RNA could induce interferon pathway genes or cause apoptosis. polyQ-TBP induced the expression of canonical RNA sensors but the downstream transcription factor, IRF3, showed a muted response. We found that expanded CAG repeat RNA is not sufficient to account for the neuronal apoptosis. Neuronal cells sense expanded CAG repeats embedded in messenger RNAs of protein-coding genes. However, polyglutamine containing protein is responsible for the interferon-mediated neuroinflammation and cell death seen in polyglutamine disease. Thus, we delineate the inflammatory role of CAG repeats in the mRNA from the resulting polyglutamine tract in the protein. Embedded in messenger RNAs of protein-coding regions, the cell senses CAG repeat expansion and induces the expression of RNA sensors and interferon-stimulated genes.
Highlights
The mammalian genome is interspersed with polymorphic repeats present in geneic and non-geneic regions
We have previously shown that the polyglutamine-TATA-box binding protein (TBP)
We have previously shown that neuronal cells expressing toxic 59Q-TBP protein induce aberrant interferon signaling resulting in Stat[1] mediated upregulation of interferon-stimulated genes (ISGs)[27]
Summary
The mammalian genome is interspersed with polymorphic repeats present in geneic and non-geneic regions. CAG repeats in the coding region of the gene, for instance, code for polyglutamine (polyQ) tracts in the corresponding protein. This polyQ tract may even be functional and. This group of nine diseases are called polyglutamine diseases. Among the polyQ diseases, Huntington’s disease (HD) which has a prevalence of 5.96–13.7 per 100,0005, is the most well studied They have been studied separately, many mechanisms of apoptosis such as autophagy[6], unfolded protein response[7] and mitochondrial dysfunction[8,9,10] have been implicated in multiple polyglutamine diseases
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