# Mechanisms of tau- and aging-induced neurological dysfunction: Focus on the nucleus

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $556,034

## Abstract

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.

## Key facts

- **NIH application ID:** 9868871
- **Project number:** 5R01AG057896-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Bess Frost
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $556,034
- **Award type:** 5
- **Project period:** 2019-02-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868871

## Citation

> US National Institutes of Health, RePORTER application 9868871, Mechanisms of tau- and aging-induced neurological dysfunction: Focus on the nucleus (5R01AG057896-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9868871. Licensed CC0.

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