# Nucleoskeleton-Cytoskeleton Connections and Cell Polarity in Aging

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $405,000

## Abstract

SUMMARY
The cytoskeleton and its connections to the nucleus play fundamental critical roles in establishing cellular
morphology, polarity, migration and substrate adhesion. We have discovered a fundamental cell polarity defect
that occurs in physiological aging and in children with the accelerated aging disorder Hutchinson-Gilford progeria
syndrome. This defect results from imbalanced connections between the nuclear lamina on the inner aspect of
the inner nuclear membrane and two major cytoskeletal protein systems: actin/microfilaments and microtubules.
These connections are mediated by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex composed
of inner nuclear membrane SUN and outer nuclear membrane KASH proteins. In aging, there is a preferential
interaction of increased SUN1 with microtubules versus SUN2 with actin/microfilaments. The parent funded grant
(R01 AG064944) for this supplemental application is designed to test the hypothesis that altered
nucleocytoskeletal connections mediated by the LINC complex cause an intrinsic cell polarity defect in aging. In
this supplement, we will expand the parent project to examine nucleocytoskeletal connections in Alzheimer
disease (AD) and related neurodegenerative dementias. The neuronal microtubule-associated protein tau
accumulates in a hyperphosphorylated form in neurons in these disorders and amyloid-beta (Aβ) oligomers
accumulate extracellularly and induce hyperphosphorylation of tau. We will therefore test the hypothesis that tau
and oligomeric Aβ alter microtubule association with LINC complexes and interfere with the generation of cell
polarity in a fibroblast model system and in primary neurons. In Aim 1, we will determine if tau and Aβ influence
the interactions of microtubules with LINC complexes and alter the generation of cell polarity. To do so, we will
use a robust fibroblast model system as proposed in the funded parent award. In Aim 2, we will determine if tau
hyperphosphorylation induced by oligomeric Aβ oligomers increases microtubule interactions with the nucleus
and perform experiments to establish if these altered interactions underlie concurrent pathological changes in
primary neurons. Finally, we will also assess the effects of SUN1 overexpression, which occurs with aging, on
primary neurons. This research will implicate tau/Aβ-induced dysfunction of the LINC complex in the
pathogenesis of AD and related dementia, and potentially identify targets for the development of therapeutic
treatments.

## Key facts

- **NIH application ID:** 10289402
- **Project number:** 3R01AG064944-03S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Gregg G Gundersen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,000
- **Award type:** 3
- **Project period:** 2019-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10289402

## Citation

> US National Institutes of Health, RePORTER application 10289402, Nucleoskeleton-Cytoskeleton Connections and Cell Polarity in Aging (3R01AG064944-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10289402. Licensed CC0.

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