# Role of arginylation in prevention of alpha synuclein-driven neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $524,288

## Abstract

Neurodegeneration affects an estimated 50 million Americans each year, significantly reducing the quality of
life for the patients and their families and costing hundreds of billions of dollars in health care. One of the
central players in neurodegeneration is alpha synuclein (a-syn), the major component of the Lewy bodies seen
in Parkinson's disease (PD) patients. Aberrant a-syn folding has been implicated in multiple forms of
neurodegeneration and recently shown to result in self-propagating prion-like action causing multiple system
atrophy (MSA) in humans. While numerous factors are believed to contribute to a-syn misfolding in different
diseases, the mechanisms that trigger a-syn transition from a normal to pathological state are not understood.
Our preliminary data demonstrate that a-syn in the normal brain undergoes arginylation, an emerging
posttranslational modification recently shown to be essential for protein homeostasis and protein-protein
interactions. We find that arginylation prevents the pathological aggregation of a-syn in neurons and that
transgenic mice lacking arginyltransferase Ate1 in the brain develop symptoms of neurodegeneration.
Consistent with these data, human PD patients show a pronounced and significant loss of Ate1 expression in
dopaminergic neurons. These results drive our central hypothesis that a-syn arginylation facilitates
normal a-syn homeostasis and that lack of a-syn arginylation leads to abnormal a-syn accumulation
thereby promoting neurodegeneration. We will test this hypothesis through the following set of integrated
specific aims that will build on the diverse expertise of our collaborative research team: 1) test the role of a-syn
arginylation in regulation of a-syn aggregation and neuropathology in neurons; 2) uncover the role of
arginylation in neurodegeneration in mouse models; and 3) establish a mechanistic link between arginylation,
a-syn, and PD pathology in human patients. Together, the proposed work will characterize a novel molecular
mechanism that potentially underlies PD and a-syn dependent neurodegeneration and will develop new
avenues for PD diagnosis and treatment.

## Key facts

- **NIH application ID:** 10145806
- **Project number:** 5R01NS102435-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Anna S Kashina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $524,288
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145806

## Citation

> US National Institutes of Health, RePORTER application 10145806, Role of arginylation in prevention of alpha synuclein-driven neurodegeneration (5R01NS102435-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145806. Licensed CC0.

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