Impact of Tau overexpression on DNA replication dynamics in centromeres of human neural progenitor cells

Aging somatic cells are characterized by specific chromosome aneuploidy, particularly involving chromosome Y (ChrY) and chromosome 21 (Chr21), which are associated with Alzheimer's disease (AD) pathology. This study investigates the role of DNA replication within centromeric regions of these chromosomes using human neural progenitor cells engineered to overexpress either wild-type (wt) or pseudo-hyper-phosphorylated (php) Tau protein. We developed a method to analyze replication dynamics in centromeric DNA. Our findings reveal that replication origins and fork pausing events are mainly located within α-satellite sequences of ChrY and Chr21, where wt and php Tau distinctly modulate origin activation and initiation. Mass spectrometry analysis on immunoprecipitated Tau identified nuclear interactors of Tau, particularly in its php form, which might directly influence the chromatin architecture and gene expression. These studies provide critical insights into the molecular mechanisms of aneuploidy in tauopathies.