# Phase separation of nuclear tau and its role in gene regulation

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $224,864

## Abstract

Project summary
Tau is a microtubule-associated protein found in neurofibrillary tangles in the brains of Alzheimer’s disease
patients. Tau can form amyloid fibrils both in vitro and in vivo and can undergo liquid-liquid phase separation in
the presence of crowding agents and nucleic acids. While much of tau research has focused on its microtubule
associated functions and aberrant aggregation in the context of Alzheimer’s disease, tau is also found in the
nucleus. Mounting evidence has suggested that nuclear tau might play a role in DNA protection, chromosome
stability, and heterochromatin formation although the molecular mechanisms behind these functions have
largely remained enigmatic.
Tau’s presence in heterochromatin is especially intriguing, since it localizes to an
environment where it would be predicted to phase separate, with other proteins known to do so. Therefore, in
this exploratory proposal,
we aim to test a hypothesis that tau might play a role in heterochromatin regulation
through a phase separation mechanism. We also hypothesize that aberrant phosphorylation and disease-
relevant mutations may disrupt this process and may lead to compromised cellular ability to regulate gene
expression. We propose to test these hypotheses through in vitro biophysical and structural assays, coupled
with cell-based experiments designed to gain better understanding of the potential functions and biophysical
properties of nuclear tau. We aim to provide a new viewpoint regarding the molecular mechanisms behind
Alzheimer’s disease that is distinct from the amyloid hypothesis and hope to inform the development of new
therapeutic and diagnostic approaches.

## Key facts

- **NIH application ID:** 10524696
- **Project number:** 1R21AG079239-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Galia Debelouchina
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $224,864
- **Award type:** 1
- **Project period:** 2022-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10524696

## Citation

> US National Institutes of Health, RePORTER application 10524696, Phase separation of nuclear tau and its role in gene regulation (1R21AG079239-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10524696. Licensed CC0.

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