NK cells clear α-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of α-synucleinopathy

The pathological hallmark of synucleinopathies, including Lewy body dementia and Parkinson's disease (PD), is the presence of Lewy bodies, which are primarily composed of intracellular inclusions of misfolded alpha-synuclein (alpha-syn) among other proteins. alpha-Syn is found in extracellular biological fluids in PD patients and has been implicated in modulating immune responses in the central nervous system (CNS) and the periphery. Natural killer (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 of PD patients and their activity is associated with disease severity; however, the role of NK cells in the context of alpha-synucleinopathies has never been explored. Here, we show that human NK cells can efficiently internalize and degrade alpha-syn aggregates via the endosomal/lysosomal pathway. We demonstrate that alpha-syn aggregates attenuate NK cell cytotoxicity in a dose-dependent manner and decrease the release of the proinflammatory cytokine, IFN-gamma. To address the role of NK cells in PD pathogenesis, NK cell function was investigated in a preformed fibril alpha-syn-induced mouse PD model. Our studies demonstrate that in vivo depletion of NK cells in a preclinical mouse PD model resulted in exacerbated motor deficits and increased phosphorylated alpha-syn deposits. Collectively, our data provide a role of NK cells in modulating synuclein pathology and motor symptoms in a preclinical mouse model of PD, which could be developed into a therapeutic for PD and other synucleinopathies.