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 (?-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 ?-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 ?-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 ?-syn aggregates and in vivo depletion of NK cells results in exacerbated synuclein pathology, neuroinflammation, and striatal degeneration in a preclinical mouse model of ?-syn aggregation. The proposed study will investigate the mechanism (s) by which NK cells reduces ?-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 ?-syn and modulate ?-syn-induced inflammation and neurotoxicity.
In Aim 2, we will determine whether NK cells are neuroprotective in a mouse model of ?-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.

Public Health Relevance

The pathological hallmark of Lewy body diseases is the presence of Lewy bodies (LBs), which are composed of abnormal aggregates of the alpha-synuclein (?-syn) protein. We propose to investigate whether natural killer (NK) cells have the capacity to protect neurons by clearing ?-syn aggregates and modulating inflammation. The completion of our study will yield ample novel data to interrogate NK cell function in age-related neurodegenerative diseases and provide a rationale for potential immune cell target strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Sieber, Beth-Anne
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University of Georgia
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