BACKGROUND Abnormal folding, aggregation and spreading of alpha-synuclein (αsyn) is a mechanistic hypothesis for the progressive neuropathology in Parkinson's disease (PD). Spread of αsyn between cells is supported by clinical, neuropathological and experimental evidence. It has been proposed that a pro-inflammatory micro-environment in response to αsyn can promote its aggregation. We have previously shown that allelic differences in the major histocompatibility complex class two transactivator (Mhc2ta) gene, located in the VRA4 locus, alter MHCII expression levels, microglial activation and antigen presentation capacity in rats upon human αsyn over-expression. In addition, Mhc2ta regulated dopaminergic neurodegeneration and the extent of motor impairment. The purpose of this study was to determine whether Mhc2ta regulates αsyn aggregation, propagation and dopaminergic pathology in an αsyn pre-formed fibril (PFF)-seeded in vivo model of PD. METHODS The DA and DA.VRA4 congenic rat strains share background genome but display differential microglial antigen presenting capacity due to different Mhc2ta alleles in the VRA4 locus. PFFs of human αsyn or BSA solution were injected unilaterally to the striatum of DA and DA.VRA4 rats two weeks after ipsilateral administration of recombinant adeno-associated virus (rAAV) vectors carrying human αsyn or GFP to the substantia nigra pars compacta. Behavioural assessment was performed at 2, 5 and 8 weeks while histological evaluation of αsyn pathology, inflammation and neurodegeneration as well as determination of serum cytokine profiles were performed at 8 weeks. RESULTS rAAV-mediated expression of human αsyn in nigral dopaminergic neurons combined with striatal PFF administration induced enhanced αsyn pathology in DA.VRA4 compared to DA rats. Mhc2ta thus significantly regulated the seeding, propagation and toxicity of αsyn in vivo. This was reflected in terms of wider extent and anatomical distribution of αsyn inclusions, ranging from striatum to the forebrain, midbrain, hindbrain and cerebellum in DA.VRA4. Compared to DA rats, DA.VRA4 also displayed enhanced motor impairment and dopaminergic neurodegeneration as well as higher levels of the proinflammatory cytokines IL-2 and TNFα in serum. CONCLUSIONS We conclude that the key regulator of MHCII expression, Mhc2ta, modulates neuroinflammation, αsyn-seeded Lewy-like pathology, dopaminergic neurodegeneration and motor impairment. This makes Mhc2ta and microglial antigen presentation promising therapeutic targets for reducing the progressive neuropathology and clinical manifestations in PD.

中文翻译：

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MHC II 类反式激活因子调节帕金森病体内大鼠模型中的种子 α-突触核蛋白病理学和多巴胺能神经变性

背景 α-突触核蛋白 (αsyn) 的异常折叠、聚集和扩散是帕金森病 (PD) 中进行性神经病理学的机制假设。临床、神经病理学和实验证据支持 αsyn 在细胞之间的传播。已经提出响应于 αsyn 的促炎微环境可以促进其聚集。我们之前已经表明，位于 VRA4 基因座的主要组织相容性复合物 2 类反式激活因子 (Mhc2ta) 基因的等位基因差异会在人 αsyn 过表达时改变大鼠的 MHCII 表达水平、小胶质细胞活化和抗原呈递能力。此外，Mhc2ta 调节多巴胺能神经变性和运动障碍的程度。本研究的目的是确定 Mhc2ta 是否调节 αsyn 聚集，αsyn 预形成原纤维 (PFF) 接种的 PD 体内模型中的增殖和多巴胺能病理学。方法 DA 和 DA.VRA4 同类大鼠品系共享背景基因组，但由于 VRA4 基因座中不同的 Mhc2ta 等位基因而显示出不同的小胶质细胞抗原呈递能力。在将携带人 αsyn 或 GFP 的重组腺相关病毒 (rAAV) 载体同侧施用至黑质致密部后两周，将人 αsyn 或 BSA 溶液的 PFF 单侧注射到 DA 和 DA.VRA4 大鼠的纹状体中。在第 2、5 和 8 周进行行为评估，而在第 8 周进行 αsyn 病理学、炎症和神经变性的组织学评估以及血清细胞因子谱的测定。结果 与 DA 大鼠相比，rAAV 介导的人 αsyn 在黑质多巴胺能神经元中的表达与纹状体 PFF 给药相结合在 DA.VRA4 中诱导了增强的 αsyn 病理学。因此，Mhc2ta 在体内显着调节了 αsyn 的播种、繁殖和毒性。这反映在 DA.VRA4 中从纹状体到前脑、中脑、后脑和小脑的更广泛的范围和 αsyn 包涵体的解剖分布上。与 DA 大鼠相比，DA.VRA4 还表现出增强的运动障碍和多巴胺能神经变性，以及血清中更高水平的促炎细胞因子 IL-2 和 TNFα。结论 我们得出结论，MHCII 表达的关键调节因子 Mhc2ta 可调节神经炎症、αsyn 种子路易样病理学、多巴胺能神经变性和运动障碍。