Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
Cell Death Dis. 2018 Oct 3;9(10):1020. doi: 10.1038/s41419-018-1066-z.
Huntingtin interaction protein 2 (HIP2) is an E2 ubiquitin-conjugating enzyme associated with neurodegenerative diseases, and HIP2 mRNA has been implicated as a potential blood biomarker for Parkinson's disease (PD). However, it is unclear whether the alteration of HIP2 expression may contribute to the development of PD, and whether the change of HIP2 in blood could reflect its expression in the brain or motor functions in PD patients. In this study, we established a mouse line with HIP2 haploinsufficiency. The reduction of the HIP2 expression led to spontaneous motor function impairment and dopaminergic neuronal loss. Furthermore, HIP2 haploinsufficiency increased the susceptibility of mice to 6-hydroxydopamine (6-OHDA) and caused severe loss of dopaminergic neurons. Interestingly, in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model for PD, we observed concurrent, highly correlated decrease of HIP2 expression in the brain and in the blood. Using blood samples from more than 300 patients, we validated the decreased HIP2 mRNA in PD patients, including de novo patients. Finally, in a 1-year, 20-patient study, we observed reversed blood HIP2 mRNA levels accompanying improved motor and overall daily functions in 75% of the PD patients with instructed Tai Chi training. Therefore, our in vivo studies have indicated HIP2 insufficiency as a contributing factor for PD, and functionally validated blood HIP2 as a useful and reversible biomarker for PD.
亨廷顿蛋白相互作用蛋白 2（HIP2）是一种与神经退行性疾病相关的 E2 泛素连接酶，HIP2mRNA 已被认为是帕金森病（PD）的潜在血液生物标志物。然而，目前尚不清楚 HIP2 表达的改变是否有助于 PD 的发展，以及血液中 HIP2 的变化是否能反映其在大脑中的表达或 PD 患者的运动功能。在这项研究中，我们建立了 HIP2 杂合不足的小鼠品系。HIP2 表达的减少导致自发性运动功能障碍和多巴胺能神经元丧失。此外，HIP2 杂合不足增加了小鼠对 6-羟基多巴胺（6-OHDA）的易感性，并导致多巴胺能神经元严重丧失。有趣的是，在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型中，我们观察到大脑和血液中 HIP2 表达的同时、高度相关的下降。使用来自 300 多名患者的血液样本，我们验证了 PD 患者包括新发患者的 HIP2mRNA 降低。最后，在一项为期 1 年、20 名患者的研究中，我们观察到在接受指导的太极拳训练的 75%的 PD 患者中，血液 HIP2mRNA 水平逆转，运动和整体日常功能得到改善。因此，我们的体内研究表明 HIP2 不足是 PD 的一个促成因素，并从功能上验证了血液 HIP2 作为 PD 的一个有用和可逆的生物标志物。
