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

Prifti, M. V.; Richardson, K.; Hussein, F. H.; Kula, T.; Stephan, A.; Wang, Y.-D.; Wang, W.; High, A. A.; Poudel, S.; Demontis, F.; Todi, S. V.

doi:10.64898/2026.10.20.760399

bioRxiv · 10.64898/2026.10.20.760399

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

Prifti, M. V.·Richardson, K.·Hussein, F. H.·Kula, T.·Stephan, A.·Wang, Y.-D.·Wang, W.·High, A. A.·Poudel, S.·Demontis, F.·Todi, S. V.

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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.

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Prifti, M. V., Richardson, K., Hussein, F. H., Kula, T., Stephan, A., Wang, Y.-D., Wang, W., High, A. A., Poudel, S., Demontis, F., Todi, S. V.. 2026-10-21. Polyglutamine-expanded TBP rewires neuronal and muscle proteomes beyond transcription in a Drosophila model of SCA17. https://doi.org/10.64898/2026.10.20.760399

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