The Lee Lab at UGA currently focuses on understanding the role of innate immune cells in the progression of Lewy body diseases. We utilize a combination of in vivo and in vitro models of synucleinopathies to uncover the mechanism of innate immune cells in neurodegenerative diseases.


Project I. To investigate the role of innate immune cells in Lewy body diseases.

Part 1) Intracerebral-initiated synucleinopathies alter immune cell profiles in the CNS and periphery. I have developed a new line of a research program investigating the role of innate immune cells in the context of synucleinopathies. Synucleinopathies include Parkinson’s disease (PD), Lewy body dementia (LBD) and multiple system atrophy (MSA), which are characterized by an accumulation of abnormally aggregated alpha-synuclein (α-syn) protein, which is the principal component of Lewy bodies. Extracellular α-syn aggregates act as a damage-associated molecular pattern (DAMP) for microglia in the CNS and also modulate immune cells in the periphery suggesting that central and peripheral immune responses play a role in synucleinopathies. However, how brain synuclein pathology affects central and peripheral immune responses have not been elucidated. I have established the relevant in vitro and in vivo model of PD using preformed fibril (PFF) alpha-synuclein (α-syn). This preclinical mouse model of PD exhibits many clinically relevant hallmarks of PD including dopaminergic cell loss, behavior deficits, and synucleinopathies. By utilizing this mouse model, we conducted a complete characterization of immune cell composition during a prodromal stage of the disease to determine whether CNS-initiated α-synucleinopathies alter immune cell profiles in the CNS and the periphery. Our data for the first time demonstrates that intracerebral-initiated synucleinopathies alter immune cell profiles not only in the CNS but also in peripheral lymphoid organs prior to neurodegeneration. These findings provide critical evidence of a link between α-syn pathology in the CNS and its effect on the peripheral immune system.

Part 2) Neuroprotective role of NK cells in a preclinical mouse model of PD. Based on our initial study showing the infiltration of peripheral immune cells into the CNS prior to DA neuronal death, natural killer (NK) cells are significantly increased in the brain with syn pathology, we have studied the role of NK cells in response to α-syn aggregates. NK cells are innate effector lymphocytes that are present in the CNS in homeostatic and pathological conditions. NK cell numbers are increased in the blood and their activity is associated with disease severity in PD patients, however, the role of NK cells in the context of α-synucleinopathy has never been explored. Here, we show that human NK cells can efficiently uptake and degrade α-syn aggregates via the endosomal/lysosomal pathway. We demonstrate that α-syn aggregates attenuate NK cell cytotoxicity in a dose-dependent manner and the release of the proinflammatory cytokine, IFN-γ. To address the role of NK cells in PD pathogenesis, NK cell function was investigated in a preformed fibril (PFF) α-syn induced mouse PD model. Our studies demonstrated that in vivo depletion of NK cells in a preclinical mouse PD model resulted in exacerbated motor deficits and increased in phosphorylated α-syn deposits. Collectively, our data provide a novel role of NK cells in modulating synuclein pathology and motor symptoms in a mouse model of PD, which could be developed into a novel therapeutic for PD and other synucleinopathies.

The long-term goal is to explain how the immune system influences PD-associated brain changes, which may represent a novel mechanism and an avenue for treating neurodegenerative diseases.

Project II. To investigate the mechanism of aged-associated changes modulating neurodegenerative diseases

Age-related changes in inflammation and metabolism in peripheral tissues and the brain have been implicated as risk factors for neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and Alzheimer’s disease-related dementia. Importantly, inflammation associated with age and metabolic syndromes does not resemble the classical inflammatory responses that are the critical processes for normal tissue homeostasis, instead, it remains as low-grade, sustained in the long time period, and promotes damaging and can lead to various pathological conditions. However, the detailed mechanisms of how age-related inflammation and associated-metabolic changes affect the onset and/or progression of the neurodegeneration have not been elucidated. Previously, I have identified a novel regulator of microglia activation and neuroinflammation, Regulator of G-protein Signaling (RGS) 10, and its neuroprotective effect on the nigrostriatal pathway. We showed the level of RGS10 in microglia significantly decreased with age. 1) We are currently investigating studies as follows: 1) Does RGS10 play a protective role in metabolic disorders by maintaining glucose tolerance and insulin sensitivity? 2) Does the loss of RGS10 with aging exaggerate chronic inflammation, metabolic syndromes and cognitive deficits in the CNS? 3) What are the detailed mechanism of RGS10 in modulating glucose homeostasis and inflammation in microglia and its role in synuclein-induced inflammation and neurotoxicity?

The long-term goal of the study is to elucidate the role of RGS10 in maintaining microglial homeostatic conditions and how we may utilize RGS10 as a therapeutic target for amyloid fibril-associated neurodegenerative diseases.

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