Tau-related Impairment of Ribosomes Biogenesis and Nuclear Transport in Early Stages of Tauopathies

Tau is a neuronal protein whose dysfunction is a hallmark of a group of neurodegenerative disorders collectively known as tauopathies, including Alzheimer’s disease (AD). While the cytoplasmic role of Tau in microtubule stabilization is well-established, its functions in other subcellular compartments remain largely unexplored. This thesis aimed to elucidate the nuclear functions of Tau and understand how its early accumulation perturbs essential molecular pathways. By integrating proteomic and molecular biology approaches, the nuclear Tau interactome has been characterized, identifying 113 interactors involved in crucial nuclear processes including nucleocytoplasmic transport and ribosome biogenesis. This analysis revealed key interactors including the nuclear transporter Importin-7 (IPO7), multiple ribosomal proteins (RPs), mitochondrial RPs, factors involved in chromatin remodeling, RNA maturation, splicing, and transport. This work demonstrated that early Tau accumulation induces a nuclear enhancement of IPO7 and alters its RPs binding profile, leading to a significant deregulation in the nuclear amount of 14 RPs and impaired ribosome assembly, evidenced by the under- representation of 24% of RPs in isolated ribosomes. These profound changes to the translational machinery rapidly occur, within hours of Tau accumulation, and represent one of the earliest molecular alterations in tauopathy. Furthermore, the altered ribosomal composition appears to drive a subsequent increase in active protein synthesis (ribosome hyperactivity), possibly mediated by the interaction between Tau and the m6 A reader, YTHDC2. Crucially, the IPO7 knock-down effectively counteracts its nuclear accumulation and restores the nuclear abundance of key ribosomal proteins, suggesting a potential strategy to correct the early ribosomal assembly defect. Collectively, these findings reveal the previously unrecognized role of Tau as a rapid and active disruptor of nuclear transport and ribosome biogenesis, identifying new mechanisms and therapeutic targets for early-stages neurodegeneration.