# Role of N-terminal acetylation in alpha synuclein stability, function, and therapeutic targeting in synucleinopathies

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $858,471

## Abstract

Project Summary
Decades of genetic and experimental evidence has placed α-synuclein (αS) as a central player in the
pathogenesis of several neurodegenerative diseases including Parkinson’s Disease (PD), Alzheimer’s Disease
(AD) and related dementias (ADRD). αS protein levels closely correlate with PD and ADRD risk, and reduction
has been shown to be protective in multiple disease models, making lowering αS levels a target for therapeutic
intervention. Despite that, there is very poor understanding of how the abundance and turnover of endogenous
αS protein is regulated. We recently found, using unbiased CRISPR screens in human cell lines and iPSC-
derived neurons, that disruption of the NatB complex resulted in a stark reduction in endogenous protein levels
and is well tolerated in human iPSC derived neurons. NatB installs N-terminal acetylation (AcN) of αS.
While AcN is a prevalent post-translational modification, its functional consequences are not well understood.
AcN has been implicated in several processes specific to αS, such as membrane binding, cell uptake, and
aggregation. Indeed, our own preliminary data support the importance of these effects and more. These results
led us to hypothesize that lack of αS AcN compromises interactions that are fundamental to its molecular
function and that pharmacological targeting of AcN represents a novel therapeutic strategy for αS’s
involvement in PD and ADRDs.
 We propose three aims that will rigorously investigate the implications of these findings on αS biology
and therapeutics. In Aim 1, we will identify the molecular interactions that are lost when αS lacks AcN. We
believe that this will provide critical insight into its biological function. We will also investigate the mechanisms
responsible for the rapid degradation of non-AcN αS compared to AcN αS. This may provide additional tools
for therapeutic reduction of pathological αS in disease and insight into αS turnover mechanisms. In Aim 2, we
will focus on understanding the outcome of NatB inhibition on the proteome and N-terminal acetylome of
human cells and neurons using quantitative proteomics approaches. Such understanding will be essential for
the development of NatB as a therapeutic target. Lastly, in Aim 3 we will develop the first NatB
pharmacological inhibitors for evaluation in vitro, and in iPSC derived neurons. We use state-of-the-art
computational approaches in combination with experimental high-throughput screening to identify molecules
that can inhibit NatB acetylation of αS with minimal effects on AcN of other proteins. These molecules will
serve as essential research tools and as lead therapeutic candidates for PD and ADRDs.

## Key facts

- **NIH application ID:** 10999561
- **Project number:** 1R01NS135829-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ronen Marmorstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $858,471
- **Award type:** 1
- **Project period:** 2024-09-13 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999561

## Citation

> US National Institutes of Health, RePORTER application 10999561, Role of N-terminal acetylation in alpha synuclein stability, function, and therapeutic targeting in synucleinopathies (1R01NS135829-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10999561. Licensed CC0.

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