How does polyglutamine expansion in TBP kill neurons?
The TATA binding protein (TBP) is a highly conserved, ubiquitously expressed General Transcription Factor which participates in expression of almost every eukaryotic gene. In humans, the TBP gene carries a CAG triplet repeat that codes for a polyglutamine stretch. Expansion of this repeat can lead to an aggregation prone TBP and neuronal cell death eventually leading to a late-onset neurodegenerative disease called Spinocerebellar Ataxia17. Although rare in occurrence, this is a member of the larger group of polyglutamine diseases which share some features like anticipation, increased severity with longer repeats and a dominant negative type of inhertiance.
We have cloned and expressed polyQ-TBP in a non-pathogenic version (16Q-TBP) and a pathogenic form (59Q-TBP). We compare these two forms in different neuronal contexts in mouse neuronal cell line, Neuro2A.
Key findings:
The miRNA, miR29a/b is downregulated in polyQ-TBP expressing cells.
Knockdown of miR-29a/b is sufficient to cause neuronal cell death and ataxia like symptoms in mice.
Stat1 and other IFN-gamma induced genes are upregulated in polyQ-TBP expressing cells.
