Polyglutamine-expanded TBP rewires neuronal and muscle proteomes beyond transcription in a Drosophila model of SCA17

Abstract

Spinocerebellar ataxia type 17 (SCA17) is an age-related neurodegenerative disorder caused by polyglutamine expansion in the TATA-binding protein (TBP). TBP is a core transcription factor, but pathogenic polyglutamine expansion likely rewires cellular programs beyond transcription. Here, we utilized Drosophila strains that express wild-type (WT) or pathogenic (SCA17) TBP in neurons or skeletal muscle, which we analyzed vs. controls via TMT mass spectrometry, profiling of eight post-translational modifications, and RNA-seq. Shared TBP-WT and TBP-SCA17 responses predominated, impacting ribosomes and mitochondria while repressing innate immunity. Disease-specific effects were narrower and tissue-dependent: SCA17 activated xenobiotic, retinoid, and glutathione-redox pathways in the CNS, but attenuated anabolism in muscle compared to TBP-WT. Many proteomic changes occurred independently of mRNA changes, implicating post-transcriptional mechanisms. Knockdown of select SCA17-regulated proteins reduced cytotoxicity, validating omics-identified modifiers of SCA17 pathology. These findings distinguish shared TBP dosage effects from disease-linked, tissue-specific polyglutamine responses and identify evolutionarily conserved targets for SCA17.