# Investigating protein phase separation and aggregation in age dependent human disease

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $780,644

## Abstract

PROJECT SUMMARY
Our overarching goal is to determine whether a newly discovered form of macromolecular organization – protein
phase-separation – contributes to the age dependency of human diseases. Recently, it has been appreciated
that many proteins related to age-dependent disease have the capacity to self-associate, condensing to form
separate ‘phase-separated’ compartments called biomolecular condensates. In vitro, some of these protein
condensates can mature over time into toxic aggregates. However, the generality of this property is unclear, as
is the degree to which it may be altered for mutant proteins associated with different ages of disease onset and
progression. Our proposal leverages comprehensive libraries of human disease alleles along with biochemistry,
cell biology, and physiological modeling to investigate and define the contribution of protein phase separation,
and aggregation, to the age dependency of human disease processes. Many human diseases involve defects
in protein folding that can be amplified with age-dependent declines in protein quality control. Moreover, many
disease alleles arise within intrinsically disordered regions of proteins, which often control phase separation
behaviors. Yet whether disease alleles commonly create imbalances in protein phase separation and
aggregation processes is unclear. Taking advantage of comprehensive libraries of mutant proteins associated
with diverse human diseases, we recently investigated the phase-separation processes of more than two
hundred disease-associated proteins. These data revealed a strong enrichment for phase separation properties
among proteins with later ages of disease onset. In targeted follow-up experiments we also validated that disease
variants in those proteins had strong effects on their phase separation and aggregation behaviors. To define the
relationships between protein phase separation and the age dependency of human disease we will conduct the
following experiments: 1. Define phase separation properties of proteins driving diverse human diseases; 2.
Characterize aggregation and prion-like ‘seeding’ associated with human disease alleles; 3. Identify protein-
autonomous and age-related systemic drivers of altered phase separation in disease. We will also investigate
whether protein phase separation provides a mechanism to understand and potentially block the impact of
dominant disease alleles in the context of aging. Together, our proposal will define biophysical and systemic
features driving phase separation and aggregation, a critical aspect of many age-related disease pathologies.

## Key facts

- **NIH application ID:** 10859986
- **Project number:** 1R01AG086495-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Daniel Jarosz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $780,644
- **Award type:** 1
- **Project period:** 2024-09-30 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10859986

## Citation

> US National Institutes of Health, RePORTER application 10859986, Investigating protein phase separation and aggregation in age dependent human disease (1R01AG086495-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10859986. Licensed CC0.

---

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