Abstract / Summary
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.