# Elucidating the role of NK cells in Lewy body diseases

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2021 · $489,561

## Abstract

PROJECT SUMMARY/ABSTRACT
Lewy body diseases including Parkinson's disease (PD), Lewy body dementia (LBD), and multiple system
atrophy are characterized by the accumulation of aggregated alpha-synuclein (α-syn) protein, which is the
principal component of Lewy bodies (LBs). Neuroinflammation is the hallmark of Lewy body diseases and the
role of the immune system has been implicated in the progression of synuclein pathology and neuropathology.
However, the role of cellular immunity in promoting neurodegeneration or exerting neuroprotection remains
unclear. We established a preclinical mouse model of α-synucleinopathy and showed a robust increase in
immune responses in the CNS and the periphery. We noted significantly increased peripheral leukocytes
including natural killer (NK) cells in the mouse model of α-synucleinopathy. As innate immune cells, NK cells
are of particular interest for neurological disorders because they are modified in the periphery and/or travel into
the CNS. It has been shown that NK cell numbers are increased in the blood of PD patients compared to age-
matched controls and their activity is associated with disease severity. However, the role of NK cells in the
context of PD has never been explored. We recently reported NK cells are present in the substantia nigra of
post mortem brains of PD and LBD patients. Based on our experimental data, NK cells efficiently clear α-syn
aggregates and in vivo depletion of NK cells results in exacerbated synuclein pathology, neuroinflammation,
and striatal degeneration in a preclinical mouse model of α-syn aggregation. The proposed study will
investigate the mechanism (s) by which NK cells reduces α-syn burden, modulate inflammation, and exert
neuroprotection in the CNS and periphery. We will use both in vitro and in vivo mouse model of
synucleinopathies to address the physiological role of NK cells in the context of Lewy body diseases. To test
our central hypothesis and achieve our objective we propose three specific aims as follows: In Aim 1, we will
investigate the mechanism by which NK cells scavenge α-syn and modulate α-syn-induced inflammation and
neurotoxicity. In Aim 2, we will determine whether NK cells are neuroprotective in a mouse model of α-syn
aggregations. In Aim 3, we will determine if peripheral NK cell infiltration into the CNS is essential for
neuroprotection. To date, there are no therapies available to slow or stop disease progression of
synucleinopathies. Our study will provide a comprehensive understanding of the role of NK cells in the context
of Lewy body diseases. Therefore, this work can have a positive impact by providing a scientific basis for
pursuing NK cells as a potential immunotherapeutic target for aged-related neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10099529
- **Project number:** 1R01NS119610-01
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Jae-Kyung Jamise Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $489,561
- **Award type:** 1
- **Project period:** 2021-02-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10099529

## Citation

> US National Institutes of Health, RePORTER application 10099529, Elucidating the role of NK cells in Lewy body diseases (1R01NS119610-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10099529. Licensed CC0.

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