PROJECT SUMMARY The nuclear envelope is a lipid bilayer that encases the genome and provides a physical boundary between the cytoplasm and the nucleoplasm. While the nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope, the smooth exterior can be interrupted by tubular invaginations of the nuclear envelope into the deep nuclear interior. Such structures are termed the “nucleoplasmic reticulum.” Increased frequency of nuclear envelope invagination occurs in disease states including various cancers, viral infections, and laminopathies, a group of heterogeneous disorders that arise due to mutations in the gene encoding lamin A (LMNA). A significant increase in the frequency of nuclear envelope invaginations in the human Alzheimer’s disease (AD) brain has recently been reported. Nuclear envelope invaginations are caused by pathogenic tau, one of the two major pathological hallmarks of AD. Pathogenic tau-induced dysfunction of the lamin nucleoskeleton drives nuclear envelope invagination and causes neuronal death, demonstrating that lamin dysfunction has severe repercussions in the adult brain. These studies suggest that maintaining proper nuclear architecture is important for survival and function of adult neurons. Our preliminary studies suggest that tau- induced nuclear envelope invagination causes a toxic increase in RNA export, and that RNA quality control is compromised in tauopathy. The proposed experiments test the overall hypothesis that tau-induced nuclear envelope invaginations cause a toxic increase in RNA export that overwhelms RNA quality control machinery. The overall goals of this proposal are to 1) Define the role of tau-induced nuclear envelope invaginations on RNA export, 2) Identify the mechanism whereby genetic and pharmacologic reduction of RNA export suppress tau-induced neurotoxicity, and 3) Determine if limited clearance of RNA transcripts by nonsense-mediated RNA decay contributes to tau and age-induced neurotoxicity. We combine studies in Drosophila, induced pluripotent stem cell (iPSC)-derived neurons from AD patients, and postmortem human AD brain tissue to address causality, test hypotheses in brains of aged animals with functional neuronal networks, and determine relevance to human AD. If our hypothesis is correct, a model will emerge that puts the lamin nucleoskeleton, nuclear envelope, and RNA handling at the central interface between aging and tauopathy. We anticipate that a multi-system investigation into the repercussions of nuclear envelope invagination will have a major impact on disorders involving nuclear architecture disruption beyond AD, aging and related tauopathies, and could lead to future development of novel, mechanism-based therapies.