# Functional Analysis of O-GlcNAc Modifications using Synthetic Protein Chemistry

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $68,654

## Abstract

Contact PD/PI: Pratt, Matthew Robert
ABSTRACT - “Functional Analysis of O-GlcNAc Modifications using Synthetic Protein Chemistry”
O-GlcNAc modification (O-GlcNAcylation) is a dynamic protein-modification that is absolutely required for
embryonic development in mammals, and is misregulated in diseases, including diabetes, neurodegeneration
and cancer. Although approximately 1,000 potential proteins are modified by O-GlcNAc, the effects of the vast
majority of these modifications on protein function are completely unknown. This critical lack of knowledge
exists in-part because traditional methods are deficient for the study of site-specific O-GlcNAcylation events.
The long-term goal of our research program is to understand the consequences of O-GlcNAcylation on proteins
that are key to human disease. The objectives of this application are to develop protein engineering strategies
that uniquely enable the generation of proteins with site-specific O-GlcNAc modifications and to apply these
methods to understand the effects of O-GlcNAcylation on the protein α-synuclein, the aggregation-prone
protein in Parkinson's disease. Our preliminary studies demonstrate that homogeneously O-GlcNAcylated
proteins can be prepared using synthetic chemistry. Furthermore, we have used synthetic protein chemistry to
demonstrate that O-GlcNAcylation blocks α-synuclein aggregation. Guided by these preliminary studies, we
will: 1) continue to develop general synthetic-strategies for the preparation of O-GlcNAcylated proteins, 2)
investigate the molecular mechanism by which O-GlcNAcylation blocks α-synuclein aggregation and 3)
determine the effects of O-GlcNAcylation on the cellular toxicity of α-synuclein. These studies are significant,
as the effects of O-GlcNAcylation are almost completely unknown. Additionally, blocking α-synuclein
aggregation is a key potential therapeutic strategy in Parkinson's disease, which lacks any current treatments
that slow the progression of neurodegeneration. Our approach is also innovative as it enables the effects of O-
GlcNAcylation to be directly tested in a site-specific fashion and can be applied to other critical proteins in the
future.
Project Summary/Abstract Page 6

## Key facts

- **NIH application ID:** 10131533
- **Project number:** 3R01GM114537-04S1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Matthew Robert Pratt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $68,654
- **Award type:** 3
- **Project period:** 2015-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131533

## Citation

> US National Institutes of Health, RePORTER application 10131533, Functional Analysis of O-GlcNAc Modifications using Synthetic Protein Chemistry (3R01GM114537-04S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10131533. Licensed CC0.

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