Translational Neurogenetics Unit, Wallenberg Neuroscience Centre, Lund University, Lund, Sweden.
Experimental Neuroinflammation Laboratory, Lund University, Lund, Sweden.
Brain Behav Immun. 2021 Jan;91:369-382. doi: 10.1016/j.bbi.2020.10.017. Epub 2020 Oct 22.
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.
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.
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.
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.
α-突触核蛋白（αsyn）的异常折叠、聚集和扩散是帕金森病（PD）进行性神经病理学的机制假说。αsyn 在细胞间的传播得到了临床、神经病理学和实验证据的支持。有人提出，针对αsyn 的炎症反应微环境可以促进其聚集。我们之前的研究表明，位于 VRA4 基因座中的主要组织相容性复合体 II 类转录激活物（Mhc2ta）基因的等位基因差异会改变大鼠中人类 αsyn 过表达时 MHCII 的表达水平、小胶质细胞的激活和抗原呈递能力。此外，Mhc2ta 调节多巴胺能神经退行性变和运动障碍的程度。本研究的目的是确定 Mhc2ta 是否调节 PD 体内 αsyn 预形成纤维（PFF）种子模型中的 αsyn 聚集、传播和多巴胺能病理学。
DA 和 DA.VRA4 同基因大鼠共享背景基因组，但由于 VRA4 基因座中不同的 Mhc2ta 等位基因，显示出不同的小胶质细胞抗原呈递能力。在对纹状体单侧注射人αsyn PFF 或 BSA 溶液之前两周，通过重组腺相关病毒（rAAV）载体将人类αsyn 或 GFP 单侧递送至黑质致密部，对 DA 和 DA.VRA4 大鼠进行单侧注射。在 2、5 和 8 周时进行行为评估，在 8 周时进行 αsyn 病理学、炎症和神经退行性变的组织学评估以及血清细胞因子谱的测定。
黑质多巴胺能神经元中 rAAV 介导的人类αsyn 表达与纹状体 PFF 给药相结合，导致 DA.VRA4 大鼠比 DA 大鼠的 αsyn 病理学增强。因此，Mhc2ta 显著调节了体内 αsyn 的种子、传播和毒性。这反映在 DA.VRA4 大鼠的 αsyn 包涵体范围更广，从纹状体到大脑前叶、中脑、后脑和小脑。与 DA 大鼠相比，DA.VRA4 大鼠还表现出更严重的运动障碍和多巴胺能神经退行性变，以及血清中促炎细胞因子 IL-2 和 TNFα 的水平升高。
我们得出结论，Mhc2ta 是 MHCII 表达的关键调节因子，调节神经炎症、αsyn 播散样路易体病理学、多巴胺能神经退行性变和运动障碍。这使得 Mhc2ta 和小胶质细胞抗原呈递成为减少 PD 进行性神经病理学和临床表现的有前途的治疗靶点。
