Elucidating the role of NK cells in Lewy body diseases

项目摘要/摘要 路易体疾病包括帕金森氏病(PD)、路易体痴呆(LBD)和多系统疾病 萎缩的特征是聚集的α-突触核蛋白(α-SYN)蛋白积聚，这是 路易体的主成分(磅)。神经炎症是路易体疾病的标志， 免疫系统的作用与突触核蛋白病理学和神经病理学的进展有关。 然而，细胞免疫在促进神经退变或发挥神经保护作用方面的作用仍然存在。 不清楚。我们建立了α-突触核苷酸病的临床前小鼠模型，并显示出 中枢和外周的免疫反应。我们注意到外周血白细胞显著增加。 包括自然杀伤(NK)细胞在内的α-突触核病小鼠模型。作为先天免疫细胞，NK细胞 对神经系统疾病特别感兴趣，因为它们在外周被修改和/或传播到 中枢神经系统。已有研究表明，PD患者血液中NK细胞数量随年龄增长而升高。 配对的对照组和他们的活动与疾病的严重性有关。然而，NK细胞在慢性粒细胞白血病中的作用 帕金森病的背景从未被探索过。我们最近报道了黑质中存在NK细胞。 帕金森病和腰椎病患者的尸检脑组织。根据我们的实验数据，NK细胞有效地清除α-SYN NK细胞的聚集和体内耗尽导致突触核蛋白病理加重，神经炎症， 以及临床前α-SYN聚集小鼠模型中的纹状体变性。拟议的研究将 探讨NK细胞降低α-SYN负荷、调节炎症、发挥免疫调节作用的机制(S) 中枢神经系统和外周的神经保护。我们将使用体外和体内的小鼠模型 在路易体疾病的背景下解决NK细胞的生理作用的联核病。为了测试 为了实现我们的目标，我们提出了三个具体目标：在目标1中，我们将 探讨NK细胞清除α-SYN并调节α-SYN诱导的炎症反应的机制 神经毒性。在目标2中，我们将确定NK细胞在α-SYN小鼠模型中是否具有神经保护作用 聚合。在目标3中，我们将确定外周NK细胞在中枢神经系统中的渗透是否对 神经保护。到目前为止，还没有可用的治疗方法来减缓或阻止疾病的进展 联体核病。我们的研究将提供对自然杀伤细胞在环境中作用的全面理解 路易身体疾病。因此，这项工作可以产生积极的影响，为 寻求NK细胞作为治疗老年神经退行性疾病的潜在免疫治疗靶点。

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