MRC Toxicology Unit, University of Cambridge, Cambridge, UK.
Cell Death Dis. 2023 Mar 22;14(3):206. doi: 10.1038/s41419-023-05729-9.
Parkinson's disease (PD) is characterised by selective death of dopaminergic (DA) neurons in the midbrain and motor function impairment. Gastrointestinal issues often precede motor deficits in PD, indicating that the gut-brain axis is involved in the pathogenesis of this disease. The features of PD include both mitochondrial dysfunction and activation of the unfolded protein response (UPR) in the endoplasmic reticulum (ER). PINK1 is a mitochondrial kinase involved in the recycling of defective mitochondria, and PINK1 mutations cause early-onset PD. Like PD patients, pink1 mutant Drosophila show degeneration of DA neurons and intestinal dysfunction. These mutant flies also lack vital proteins due to sustained activation of the kinase R-like endoplasmic reticulum kinase (dPerk), a kinase that induces the UPR. Here, we investigated the role of dPerk in intestinal dysfunction. We showed that intestinal expression of dPerk impairs mitochondrial function, induces cell death, and decreases lifespan. We found that suppressing dPerk in the intestine of pink1-mutant flies rescues intestinal cell death and is neuroprotective. We conclude that in a fly model of PD, blocking gut-brain transmission of UPR-mediated toxicity, is neuroprotective.
帕金森病（PD）的特征是中脑多巴胺能（DA）神经元的选择性死亡和运动功能障碍。胃肠道问题常在 PD 出现运动缺陷之前出现，表明肠道-大脑轴参与了这种疾病的发病机制。PD 的特征包括线粒体功能障碍和内质网（ER）中未折叠蛋白反应（UPR）的激活。PINK1 是一种参与缺陷线粒体回收的线粒体激酶，PINK1 突变导致早发性 PD。与 PD 患者一样，pink1 突变果蝇表现出 DA 神经元退化和肠道功能障碍。这些突变苍蝇还由于激酶 R 样内质网激酶（dPerk）的持续激活而缺乏重要的蛋白质，dPerk 是一种诱导 UPR 的激酶。在这里，我们研究了 dPerk 在肠道功能障碍中的作用。我们表明，肠道表达 dPerk 会损害线粒体功能、诱导细胞死亡并降低寿命。我们发现，抑制 pink1 突变果蝇肠道中的 dPerk 可挽救肠道细胞死亡并具有神经保护作用。我们得出结论，在 PD 的果蝇模型中，阻断 UPR 介导的毒性的肠道-大脑传递具有神经保护作用。
