近日，加拿大蒙特利尔大学和麦吉尔大学的联合研究团队发现，在Pink1^-/-小鼠中，肠道感染会触发帕金森病样症状，从而揭示了肠道炎症和神经退行性疾病的关联。该项研究成果发表在2019年7月25日出版的《自然》上。

该项研究表明，Pink^-/-小鼠中的革兰氏阴性细菌的肠道感染参与了线粒体抗原呈递和自身免疫机制，从而在外周和脑中建立细胞毒性线粒体特异性CD8⁺T细胞。值得注意的是，这些被感染的小鼠体内，纹状体中多巴胺突触额密度急剧下降，并且受到运动损伤的影响，采用左旋多巴胺治疗后能够实现恢复逆转。这些数据都支持PINK1是免疫系统抑制因子的观点。文章提供了一个病理生理性模型，其中肠道感染是帕金森病的一个诱发因素，进一步突出了肠脑轴在疾病中的相关性。

  据了解，帕金森病是一种神经退行性疾病，其运动症状与黑质致密部中多巴胺能神经元的丧失有关。尽管到目前为止，引发多巴胺能神经元丧失的机制尚不清楚，但线粒体功能障碍和炎症仍被认为起着关键作用。早期发作的帕金森病与PINK1激酶和PRKN泛素连接酶基因的突变有关。PINK1和Parkin（由PRKN编码）参与了培养细胞中受损线粒体的清除。但是，最近通过基因敲除和基因敲入的小鼠模型获得的证据显示，关于PINK1和Parkin对体内线粒体自噬的贡献是相互矛盾的。此前已有研究表明，PINK1和Parkin通过抑制线粒体抗原的呈递在适应性免疫中发挥了关键作用，这表明自身免疫机制参与了帕金森的病因学。

附：英文原文

Title: Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1 −/− mice

Author: Diana Matheoud, Tyler Cannon, Aurore Voisin, Anna-Maija Penttinen, Lauriane Ramet, Ahmed M. Fahmy, Charles Ducrot, Annie Laplante, Marie-Jose Bourque, Lei Zhu, Romain Cayrol, Armelle Le Campion, Heidi M. McBride, Samantha Gruenheid, Louis-Eric Trudeau, Michel Desjardins

Issue&Volume: Volume 571 Issue 7766

Abstract: Parkinsons disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles. An early-onset form of Parkinsons disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens, which suggests that autoimmune mechanisms participate in the aetiology of Parkinsons disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1/ mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with l-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinsons disease, which highlights the relevance of the gutbrain axis in the disease.

DOI: 10.1038/s41586-019-1405-y

Source: https://www.nature.com/articles/s41586-019-1405-y