# Integrating pathogenic mechanisms in Parkinson's disease

> **NIH NIH R01** · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · 2022 · $335,344

## Abstract

ABSTRACT
α-synuclein expression, c-Abl activation, and neuronal glutathione levels are each
recognized as contributory factors in Parkinson’s disease, but how these factors interact is
poorly understood. This knowledge gap is of basic and therapeutic relevance because
these interactions may define a final common pathway in Parkinson’s disease
pathogenesis. Glutathione is used by neurons to both scavenge reactive oxygen species
and repair oxidatively damage proteins. In Parkinson’s disease, the accumulation of α-
synuclein oligomers is associated with glutathione depletion, oxidative stress, and neuronal
death. α-synuclein aggregate formation is promoted by c-Abl, a tyrosine kinase that is in
turn activated by oxidative stress. We hypothesize that α-synuclein aggregates drive
reactive oxygen species formation through metal-catalyzed processes, and that the
resulting glutathione depletion contributes to α-synuclein aggregation and c-Abl activation in
a feed-forward manner. We will test this hypothesis using cell culture models in which α-
synuclein aggregates, thiol redox state, and c-Abl activity can be independently manipulated
and monitored. We will also employ two novel double-transgenic mouse strains that permit
evaluation of a-synuclein aggregation and its associated pathology in the setting of (1)
deficient NADPH oxidase activity, and (2) reduced neuronal glutathione levels. These
strains, in combination with novel pharmacological tools, will allow us to identify cause-
effect relationships between neuronal oxidative stress, α-synuclein aggregation, and c-Abl
activity in vivo.
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## Key facts

- **NIH application ID:** 10430048
- **Project number:** 5R01NS105774-05
- **Recipient organization:** NORTHERN CALIFORNIA INSTITUTE/RES/EDU
- **Principal Investigator:** RAYMOND A SWANSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $335,344
- **Award type:** 5
- **Project period:** 2018-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430048

## Citation

> US National Institutes of Health, RePORTER application 10430048, Integrating pathogenic mechanisms in Parkinson's disease (5R01NS105774-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10430048. Licensed CC0.

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