ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Tau-induced increase in promoter-proximal RNA polymerase II pausing is linked to suppressed expression of long neuronal genes in a Drosophila tauopathy model
1. Biochemistry Department, Purdue University, West Lafayette, United States
2. Purdue University Purdue Institute for Integrative Neuroscience, West Lafayette, United States
3. Purdue University Institute for Cancer Research, West Lafayette, United States
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Abstract
Tauopathies, including Alzheimer's disease, are age-related neurodegenerative disorders characterized by abnormal phosphorylation and buildup of microtubule-associated protein tau. Gene expression dysregulation is a key molecular feature of tauopathies, but how aging and disease interact to disrupt crucial transcriptional regulators and pathways remains largely unknown. Here, we examined how pathological tau affects gene expression programs in age-related neurodegenerative disease using a well-established Drosophila melanogaster tauopathy model with neuronal expression of the toxic human tauR406W. Transcriptomic analysis of tau-expressing fly heads showed a preferential downregulation of long neuronal genes with long introns. Notably, we found that these downregulated genes in the tauopathy model are marked by increased accumulation of initiating RNA polymerase II (RNAP II) near the transcription start site and reduced elongating RNAP II within gene bodies, indicating a problem with the transition from initiation to elongation. By calculating an RNAP II Pause Index (PI) for each gene, we identified a strong link between promoter-proximal RNAP II stalling, gene expression deficits, and gene length in the tauopathy model. Overall, we have uncovered the genomic and transcriptomic features of tau-dependent downregulated genes and identified increased RNAP II promoter-proximal stalling as a significant mechanism of transcription stress in tauopathy.
Summary
Keywords
Aging, Alzheimer's disease, Drosophila, Gene Expression, neurodegeneration, Promoter-proximal pausing, Taupathy
Received
09 April 2026
Accepted
13 August 2026
Copyright
© 2026 Cottingham, Goodarzi, Fries, Lirushie and Hall. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hana Hall
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