# Diversity Supplement to R01NS105774

> **NIH NIH R01** · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · 2021 · $73,047

## Abstract

ABSTRACT
Both α-synuclein expression and neuronal glutathione levels are recognized as crucial
factors in the pathogenesis of Parkinson’s disease (PD), but how these factors interact is
poorly understood. This knowledge gap is of therapeutic relevance, because
pharmacological agents for restoring neuronal glutathione levels are clinically available. In
PD, the accumulation of α-synuclein oligomers or higher-order aggregates is associated
with oxidative stress, glutathione depletion, and neuronal death. Additionally, the clearance
of α-synuclein is impaired by the tyrosine kinase c-Abl, which is activated by oxidative
stress. Glutathione is the dominant thiol redox species and is used by cells to both
scavenge reactive oxygen species and repair oxidatively damage proteins. Here we aim to
identify specific cause-effect relationships between neuronal thiol redox status, c-Abl
activation, and α-synuclein - mediated pathology. Our underlying hypothesis is that α-
synuclein aggregates drive reactive oxygen species formation through metal-catalyzed
processes, and the resulting glutathione depletion contributes to α-synuclein aggregation in
a feed-forward manner. The studies will use cell culture models in which both α- synuclein
expression and thiol redox state can be controlled and monitored. The studies will also use
a novel double-transgenic mouse generated by crossing the Thy-1 α-synuclein “Line 61”
mouse, which exhibits α-synuclein aggregate formation, with the EAAT3-/- mouse, which
exhibits low neuronal glutathione levels. The glutathione defect in these mice can be
reversed with oral cysteine pro-drugs. This permits both experimental manipulation of
neuronal thiol redox state in situ, and an assessment of potential disease -modifying
therapeutic agents for PD.
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## Key facts

- **NIH application ID:** 10350351
- **Project number:** 3R01NS105774-03S1
- **Recipient organization:** NORTHERN CALIFORNIA INSTITUTE/RES/EDU
- **Principal Investigator:** RAYMOND A SWANSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $73,047
- **Award type:** 3
- **Project period:** 2021-06-07 → 2022-06-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10350351

## Citation

> US National Institutes of Health, RePORTER application 10350351, Diversity Supplement to R01NS105774 (3R01NS105774-03S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10350351. Licensed CC0.

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