한빛사논문
- 조회1,491
Rachael H. Earlsa,1 , Kelly B. Meneesa,1, Jaegwon Chunga,1, Claire-Anne Gutekunstb, Hyun Joon Leec,d, Manuel G. Hazimb, Balázs Radae, Levi B. Woodf,g, and Jae-Kyung Leea,2
a Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602; b Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322; c Department of Neurology, University of Mississippi Medical Center, Jackson, MS 39216; d Research Service, G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS 39216; e Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602; f Coulter Department of Biomedical Engineering, Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332; and g Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
1R.H.E., K.B.M., and J.C. contributed equally to this work.
2To whom correspondence may be addressed.
Abstract
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 α-synuclein (α-syn) among other proteins. α-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 α-synucleinopathies has never been explored. Here, we show that human NK cells can efficiently internalize 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 decrease 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 α-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 α-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.
Parkinson’s disease, natural killer cell, α-synuclein, Lewy bodies, synucleinopathies
논문정보
- Research article
- 2020년 01월 (BRIC 등록일 2020-01-15)
- 국외 연구진
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