MAPT mutations are associated with rDNA transcriptional hyperactivation and nucleolar stress in cellular models
Abstract
Tau is traditionally known for its role in microtubule stabilisation, with its pathological aggregation central to tauopathies such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Recent evidence suggests that tau also plays important nuclear and nucleolar roles, yet the implications of tau pathology on nucleolar function remain poorly understood. Here, we show that tau localises to the nucleolus in both differentiated SH-SY5Y cells and human iPSC-neurons, and that disease-associated MAPT mutations are associated with increased nucleolar tau accumulation (P301S, S305N, and IVS 10 + 16). Using high-content imaging, we found that mutant tau expression was associated with structural expansion of the nucleus and nucleolus, together with upregulation of key markers from all three nucleolar sub-compartments, consistent with increased nucleolar activity. qPCR and nucleolar RNA-selective dye staining demonstrated increased rDNA transcription and rRNA processing, consistent with enhanced nucleolar biosynthetic output in mutant tau-expressing cells. This increase in nucleolar activity was accompanied by markers of nucleolar stress and apoptosis, including p53 stabilisation, caspase 3/7 activation, and TUNEL positivity. Notably, pharmacological inhibition of RNA polymerase I in the inducible SH-SY5Y model attenuated caspase 3/7 activity, supporting a functional contribution of elevated rDNA transcriptional activity to downstream apoptotic signalling. Together, these findings identify altered nucleolar homeostasis as a feature associated with mutant tau expression and support a potential contribution of nucleolar dysregulation to disease-associated cellular dysfunction in MAPT-linked FTD.
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BibTeX
@article{muhammad2026mapt,
title = {{MAPT mutations are associated with rDNA transcriptional hyperactivation and nucleolar stress in cellular models}},
author = {Zaid Muhammad and Yan Gu and Suleiman H. Kwairanga and Laura J. Bailey and Amna Khan and Mohammad Nasser and Dana Aljarrah and Muruj Barri and Charles Arber and Selina Wray and Louise C. Serpell and Celeste M. Karch and Mahmoud B. Maina},
journal = {Translational Psychiatry},
year = {2026},
month = oct,
doi = {10.1038/s41398-026-04484-7},
url = {https://www.nature.com/articles/s41398-026-04484-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - MAPT mutations are associated with rDNA transcriptional hyperactivation and nucleolar stress in cellular models
AU - Zaid Muhammad
AU - Yan Gu
AU - Suleiman H. Kwairanga
AU - Laura J. Bailey
AU - Amna Khan
AU - Mohammad Nasser
AU - Dana Aljarrah
AU - Muruj Barri
AU - Charles Arber
AU - Selina Wray
AU - Louise C. Serpell
AU - Celeste M. Karch
AU - Mahmoud B. Maina
PY - 2026
DA - 2026/10/11
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04484-7
UR - https://www.nature.com/articles/s41398-026-04484-7
AB - Tau is traditionally known for its role in microtubule stabilisation, with its pathological aggregation central to tauopathies such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Recent evidence suggests that tau also plays important nuclear and nucleolar roles, yet the implications of tau pathology on nucleolar function remain poorly understood. Here, we show that tau localises to the nucleolus in both differentiated SH-SY5Y cells and human iPSC-neurons, and that disease-associated MAPT mutations are associated with increased nucleolar tau accumulation (P301S, S305N, and IVS 10 + 16). Using high-content imaging, we found that mutant tau expression was associated with structural expansion of the nucleus and nucleolus, together with upregulation of key markers from all three nucleolar sub-compartments, consistent with increased nucleolar activity. qPCR and nucleolar RNA-selective dye staining demonstrated increased rDNA transcription and rRNA processing, consistent with enhanced nucleolar biosynthetic output in mutant tau-expressing cells. This increase in nucleolar activity was accompanied by markers of nucleolar stress and apoptosis, including p53 stabilisation, caspase 3/7 activation, and TUNEL positivity. Notably, pharmacological inhibition of RNA polymerase I in the inducible SH-SY5Y model attenuated caspase 3/7 activity, supporting a functional contribution of elevated rDNA transcriptional activity to downstream apoptotic signalling. Together, these findings identify altered nucleolar homeostasis as a feature associated with mutant tau expression and support a potential contribution of nucleolar dysregulation to disease-associated cellular dysfunction in MAPT-linked FTD.
SN - 2158-3188
ER -