# Mechanisms of Neurodegeneration in Lewy Body Disorders

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $385,000

## Abstract

PROJECT SUMMARY
One major obstacle to halting neurodegeneration in synucleinopathies like Parkinson's Disease (PD) and
Dementia with Lewy Bodies (DLB) is a lack of understanding of why vulnerable cell populations die. Although
aggregated alpha-synuclein Lewy pathology occurs within specific neurons, and their dysfunction or
degeneration leads to symptoms in these diseases, how Lewy pathology itself plays a role is unclear. Recent
work by the Unni lab has discovered a previously unrecognized function for the protein alpha-synuclein in
repairing nuclear DNA double-strand breaks (DSB), by using newly developed in vivo multiphoton imaging
techniques to study alpha-synuclein aggregation in mice. These approaches have now been extended (for the
first time) to study DNA repair in living mouse brain. The unexpected function for alpha-synuclein immediately
suggests an exciting new hypothesis for the role of aggregated alpha-synuclein Lewy inclusions in
neurodegeneration. This central hypothesis is that in disease, alpha-synuclein protein is sequestered in
cytoplasmic Lewy bodies, decreasing its nuclear DSB repair function and leading to cell death of Lewy body-
containing neurons. Furthermore, it is proposed that the source of fibrillar α-synuclein that initially seeds Lewy
body formation comes from dysregulated DSB repair. The preliminary data suggest this complex
interrelationship, with alpha-synuclein aggregation causing dysregulated DSB repair and vice versa. Although
completely novel, this link between alpha-synuclein and DSB repair could explain previously poorly understood
associations between human and mouse mutations in the DSB repair protein Ataxia-Telangiectasia Mutated
and alpha-synuclein aggregation, and between specific synuclein family members and cancer (e.g. alpha-
synuclein & melanoma, gamma-synuclein & breast cancer). This proposal will use a combination of advanced
imaging approaches in purified, reconstituted in vitro systems, in mouse brain in vivo, and in mouse & human
(PD, DLB) fixed tissue to test how alpha-synuclein mediates DSB repair (Aim 1), how loss of nuclear α-
synuclein function after cytoplasmic Lewy inclusion formation dysregulates DSB repair and contributes to
neuronal cell death (Aim 2), and how dysregulated DSB repair can lead to Lewy inclusion formation (Aim 3).
Overall, this project is innovative because it uses powerful, new in vivo experimental approaches to test a
fundamentally new hypothesis for how alpha-synuclein aggregation into Lewy pathology is related to
neurodegeneration. This contribution will be significant because it will provide a completely new set of targets
for treating these debilitating neurodegenerative disorders that focuses on the DSB repair pathway, and
because understanding alpha-synuclein-mediated DSB repair in detail will increase our basic science
knowledge of this important biological process.

## Key facts

- **NIH application ID:** 10112964
- **Project number:** 5R01NS102227-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Vivek Unni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112964

## Citation

> US National Institutes of Health, RePORTER application 10112964, Mechanisms of Neurodegeneration in Lewy Body Disorders (5R01NS102227-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10112964. Licensed CC0.

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