MECHANISMS OF TAU AND AGING-INDUCED NEUROLOGICAL DYSFUNCTION: FOCUS ON THE NUCLEUS

The nuclear envelope is a lipid bilayer that encases the genome and provides a physical boundary betweenthe cytoplasm and the nucleoplasm. While the nucleus is typically depicted as a sphere encircled by a smoothsurface of nuclear envelope, the smooth exterior can be interrupted by tubular invaginations of the nuclearenvelope into the deep nuclear interior. Such structures are termed the ?nucleoplasmic reticulum.? Increasedfrequency 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 laminA (LMNA). A significant increase in the frequency of nuclear envelope invaginations in the human Alzheimer?sdisease (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 laminnucleoskeleton drives nuclear envelope invagination and causes neuronal death, demonstrating that lamindysfunction has severe repercussions in the adult brain. These studies suggest that maintaining proper nucleararchitecture 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 iscompromised in tauopathy. The proposed experiments test the overall hypothesis that tau-induced nuclearenvelope 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 onRNA export, 2) Identify the mechanism whereby genetic and pharmacologic reduction of RNA export suppresstau-induced neurotoxicity, and 3) Determine if limited clearance of RNA transcripts by nonsense-mediatedRNA decay contributes to tau and age-induced neurotoxicity. We combine studies in Drosophila, inducedpluripotent stem cell (iPSC)-derived neurons from AD patients, and postmortem human AD brain tissue toaddress causality, test hypotheses in brains of aged animals with functional neuronal networks, and determinerelevance 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 thata multi-system investigation into the repercussions of nuclear envelope invagination will have a major impacton disorders involving nuclear architecture disruption beyond AD, aging and related tauopathies, and couldlead to future development of novel, mechanism-based therapies.