Département de Pathologie et Biologie Cellulaire, Faculté de Médecine, Université de Montréal, Montréal, Quebec, Canada.
Département de Neurosciences, CRCHUM, Université de Montréal, Montréal, Quebec, Canada.
Nature. 2019 Jul;571(7766):565-569. doi: 10.1038/s41586-019-1405-y. Epub 2019 Jul 17.
Parkinson's 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 Parkinson's 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 Parkinson's 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 Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease.
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多巴胺能神经元的丧失有关。尽管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被认为起着关键作用。一种早发性帕金森病与 PINK1 激酶和 PRKN 泛素连接酶基因的突变有关。PINK1 和 Parkin（由 PRKN 编码）参与培养细胞中受损线粒体的清除，但使用敲除和敲入小鼠模型获得的最新证据导致了关于 PINK1 和 Parkin 在体内线粒体自噬中的作用的相互矛盾的结果。先前的研究表明，PINK1 和 Parkin 通过抑制线粒体抗原的呈递在适应性免疫中起关键作用，这表明自身免疫机制参与了帕金森病的发病机制。在这里，我们表明 Pink1 小鼠的革兰氏阴性菌肠道感染会引发线粒体抗原呈递和自身免疫机制，从而在外周和大脑中引发细胞毒性线粒体特异性 CD8 T 细胞的建立。值得注意的是，这些小鼠的纹状体中多巴胺能轴突末梢的密度明显下降，并且受到运动障碍的影响，用 L-DOPA 治疗后可逆转。这些数据支持 PINK1 是免疫系统的抑制剂的观点，并提供了一个病理生理学模型，其中肠道感染是帕金森病的触发事件，这突出了肠道-大脑轴在该疾病中的相关性。
