PINK1 deficiency rewires early immune responses in a mouse model of Parkinson's disease triggered by intestinal infection

Parkinson’s disease is characterized by a period of non-motor symptoms, including gastrointestinal dysfunction, preceding motor deficits by decades. This long prodrome is suggestive of peripheral immunity involvement in the initiation of disease. We previously developed a model system in PINK1 KO mice displaying PD-like motor symptoms at late stages following intestinal infections. Herein, we map the initiating immune events at the site of infection in this model. Using single-cell RNAseq, we demonstrate that peripheral myeloid cells are the earliest highly dysregulated immune cell type in PINK1 KO infected mice followed by an aberrant T cell response shortly after. We elucidate an increased propensity for antigen presentation mediated by myeloid-CD8+ T cell interaction. PINK1 KO activated myeloid cells acquire a proinflammatory profile inducing cytotoxic T cell responses. Together, our study provides the first evidence that PINK1 is a key regulator of immune functions in the gut underlying early PD-related disease mechanisms.帕金森病（Parkinson’s disease）以一段存在非运动症状的前驱病程为特征，其中涵盖胃肠功能障碍，且该阶段可比运动功能缺损早数十年出现。这种漫长的前驱期提示外周免疫参与了疾病的起始过程。我们此前在PINK1基因敲除（PINK1 KO）小鼠中构建了一套模型系统，该模型小鼠在肠道感染后的晚期阶段可表现出帕金森病样的运动症状。在此研究中，我们对该模型中感染部位的起始免疫事件进行了全景解析。通过单细胞RNA测序（single-cell RNAseq），我们证实，在感染后的PINK1基因敲除小鼠中，外周髓系细胞是最早出现显著免疫失调的免疫细胞类型，随后不久便会出现异常的T细胞应答。我们阐明了髓系细胞与CD8阳性T细胞（CD8+ T cell）相互作用所介导的抗原呈递倾向显著升高的现象。PINK1基因敲除小鼠的活化髓系细胞会获得促炎表型，进而诱导细胞毒性T细胞应答。综上，本研究首次提供证据表明，PINK1是肠道免疫功能的关键调控因子，其参与了早期帕金森病相关的疾病发病机制。