Parkinson’s disease (PD) is the most common neurodegenerative movement disorder in the United States. While the combined direct and indirect cost of PD is estimated to be nearly $52 billion per year in the United States alone, there are no disease modifying therapies currently available. There is increasing evidence for a central role of the immune system in the pathophysiology of PD. Human post-mortem tissue and animal models of PD demonstrate exacerbated inflammation and immune responses including prominent microgliosis, increased expression of pro-inflammatory cytokines, IgG deposition, and peripheral lymphocyte infiltration. While extensive efforts have been made to characterize the immunological responses of microglia in PD, less is known about the role of peripheral immune cells. Natural Killer (NK) cells are lymphocytes with pleiotropic functions including the recognition and elimination of transformed cells, anti-microbial defense, senescent cell clearance, resolution of inflammation, and modulation of adaptive immunity. While NK cells show immense therapeutic potential in neurological disorders including glioblastoma and multiple sclerosis, the function of NK cells in PD has never been explored. The objectives of this dissertation were to 1) develop a pre-clinical mouse model of PD 2) characterize the inflammatory profile within our model 3) Determine the role NK cells play in the progression of PD pathogenesis 4) Interrogate the effects of ageing on NK cell frequency and function. Through our data, we revealed that central and peripheral inflammation is an early event in PD that precedes neurodegeneration. Importantly, we observed NK cell numbers are increased five-fold in the brain of our murine model of PD compared to controls. We discovered that ageing (a primary risk factor for neurodegenerative disease) promotes a significant reduction in the frequency of NK cells and a redistribution of NK cell receptors that are critical for maintaining homeostatic function. Furthermore, systemic NK cell depletion in our synucleinopathy model led to augmented pathology, neuroinflammation, neurodegeneration, and motor deficits. Collectively, these findings suggest that NK cells may play a protective role in PD. These studies strengthen the current understanding of NK cell function in neurodegenerative diseases and provide a novel therapeutic target for PD.