# Are all Protein Aggregates Toxic?

> **NIH NIH R15** · MICHIGAN TECHNOLOGICAL UNIVERSITY · 2022 · $439,333

## Abstract

PROJECT SUMMARY
Abnormal aggregation and deposition of misfolded proteins have been recognized as a common pathological
hallmark of several neurodegenerative diseases. The goal of this project is to identify unique physicochemical
properties of aggregates, shared by a large number of structurally diverse proteins (e.g. Aβ42 peptide, insulin
and lysozyme), that are toxic. In general, the scientific community agrees that soluble aggregates of proteins,
especially those that are in the form of proto-fibrils, are noxious. These aggregates can cause toxicity by
several mechanisms such as, aberrant interaction with cellular membranes, organelles, interaction with other
proteins that may be critical for cellular functions, or by clogging the protein degradation and clearing
pathways. However, there is paucity in literature showing a clear correlation between aggregated proteins
shape (e.g. amorphous, globular, or fibril), flexibility (e.g. flexible, or rigid), size (e.g. monomer, oligomer, or
fibril), and hydrophobicity, with its associated toxicity. Our findings on Aβ42 peptide aggregation and toxicity
shows that increased surface hydrophobicity of protein aggregates can contribute to an increase in cellular
toxicity. We hypothesize that flexible protein aggregates with increased surface hydrophobicity may hold the
key to cellular toxicity. To test this hypothesis, we will use simple but unrelated proteins (e.g. insulin and
lysozyme) which are normally not toxic and compare the properties of the aggregates of these proteins with
Aβ42 peptide aggregates whose role in Alzheimer’s disease is well known. We will generate diverse
aggregated structures from these proteins, characterize their biochemical and biophysical properties including
size, shape, flexibility, relative hydrophobicity, and measure their associated toxicity. This will also help us
address: “Is it the sequence or the unique physicochemical properties of the aggregated protein that is critical
for its toxicity”. As a result, it will help us identify key physicochemical properties shared by protein aggregates
that are central to their toxicity.

## Key facts

- **NIH application ID:** 10580153
- **Project number:** 1R15GM148964-01
- **Recipient organization:** MICHIGAN TECHNOLOGICAL UNIVERSITY
- **Principal Investigator:** Ashutosh Tiwari
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $439,333
- **Award type:** 1
- **Project period:** 2022-09-22 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10580153

## Citation

> US National Institutes of Health, RePORTER application 10580153, Are all Protein Aggregates Toxic? (1R15GM148964-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10580153. Licensed CC0.

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