# Investigating nucleo-cytoplasmic partitioning in Alzheimer's disease and aging

> **NIH NIH R21** · BROWN UNIVERSITY · 2020 · $198,125

## Abstract

PROJECT SUMMARY/ABSTRACT
Nucleo-cytoplasmic partitioning of proteins is an emerging intracellular process with crucial roles
in Alzheimer’s disease and aging. Karyopherins mediate proper partitioning by transporting
proteins across the nuclear pore. Pharmacological modulation of karyopherins provides a new
approach for therapies against Alzheimer’s disease.
 Recent studies in model organisms and mammalian cells have uncovered that several
neurodegenerative diseases display dysfunctional nucleo-cytoplasmic protein partitioning. We
have reported that the conserved karyopherin XPO1 accelerates aging by promoting the nuclear
export of longevity-associated transcription factors, thereby preventing the maintenance of
proteostatic mechanisms. Specifically, we showed that inhibiting XPO1 leads to lifespan
extensions and results in enhanced proteostasis across phyla, in part via the autophagy-
lysosomal pathway. Levels of XPO1 are reduced in long-lived animals and our recent data
suggest that XPO1-mediated lifespan modulation relies on fundamental changes in transcriptome
and proteome partitioning as well as nucleoli re-organization, which results in altered ribosomal
biogenesis. Thus, we hypothesize that XPO1 coordinately modulates the nucleo-cytoplasmic
partitioning of proteins and nucleoli formation, thereby regulating compartment-specific protein
functions, ribosomal biogenesis, active mRNA translation and consequently lifespan.
 To address this hypothesis, we propose to conduct a global characterization of protein
partitioning and specification and its impact on proteostasis and aging. We will combine cutting-
edge genetics and biochemical approaches in C. elegans and mammalian cells to characterize
the nucleo-cytoplasmic partitioning of proteins during aging (Aim 1) and, ultimately, to uncover
new modulators of nucleolar function with potential benefits against Alzheimer’s disease (Aim 2).
 These proposed studies are significant as they address an important question in aging related
to the role and regulation of nucleo-cytoplasmic partitioning and nucleoli function during organism
aging. Our approaches are innovative since we utilize C. elegans and mammalian cells in parallel
to quickly identify specific protein translation and partitioning of proteins with roles in aging and to
uncover pharmacological strategies to modulate nucleolar and ribosomal dynamics and
preventing Alzheimer’s disease.

## Key facts

- **NIH application ID:** 10042748
- **Project number:** 1R21AG068922-01
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Louis Rene Lapierre
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $198,125
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10042748

## Citation

> US National Institutes of Health, RePORTER application 10042748, Investigating nucleo-cytoplasmic partitioning in Alzheimer's disease and aging (1R21AG068922-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10042748. Licensed CC0.

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