# Mapping tauopathy-induced changes in subcellular proteostasis with compartment-targeted sensors

> **NIH NIH R21** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $500,500

## Abstract

PROJECT SUMMARY.
Decline in proteostasis is a defining feature of cellular aging and of age-related diseases. Recent studies have
shown that protein quality control in each organelle is impacted by organelle-specific challenges but also
interconnected with proteostasis in other cell compartments. Depending on the context, this organelle
interdependence has been proposed to preserve or derange protein quality control. However, the investigation
of subcellular proteostasis has been limited by the lack of suitable transgenic reporters for monitoring protein
quality control in multiple cell compartments in vivo.
 Alzheimer’s disease (AD) is defined by the action of aggregation-prone pathogenic proteins that perturb
proteostasis. Despite a confined subcellular localization, these pathogenic proteins impact the function of
multiple organelles and compartments across the cell. However, the role of inter-organelle crosstalk in AD
remains largely unexplored. Specifically, it remains unknown whether perturbation of proteostasis in a specific
cell compartment by an AD-linked pathogenic protein reverberates on protein quality control in other
compartments.
 In our preliminary studies, we have generated transgenic compartment-targeted misfolding-prone proteins
that, depending on the experimental design, can be used as sensors of subcellular proteostasis or as tools to
offset proteostasis. By using these novel probes, we have found that aging differentially affects proteostasis in
the nucleus, endoplasmic reticulum, mitochondria, and cytoplasm. On this basis, we now propose to determine
how AD pathogenic proteins affect protein quality control in distinct subcellular compartments and, conversely,
how compartment-restricted derangement of proteostasis impacts AD. For these studies, we will examine
microtubule-associated protein tau (MAPT) mutants that have been linked to the onset of an AD-related condition
(frontotemporal dementia) in humans. Specifically, we propose to determine whether tauopathy modulates
proteostasis in distinct cell compartments; how aging synergizes with AD-related pathogenic tau in regulating
subcellular proteostasis; and whether, conversely, protein misfolding in distinct subcellular compartments
differentially impacts tauopathy. Altogether, these studies promise to provide fundamental understanding on how
mutant tau cross-regulates subcellular proteostasis, which may be relevant for understanding how organelle and
cell function are deranged in AD.

## Key facts

- **NIH application ID:** 10526120
- **Project number:** 1R21AG079267-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Fabio Demontis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $500,500
- **Award type:** 1
- **Project period:** 2022-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526120

## Citation

> US National Institutes of Health, RePORTER application 10526120, Mapping tauopathy-induced changes in subcellular proteostasis with compartment-targeted sensors (1R21AG079267-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10526120. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*