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Cell Death Dis. 2018 Oct 3;9(10):1020. doi: 10.1038/s41419-018-1066-z.

Reduction of HIP2 expression causes motor function impairment and increased vulnerability to dopaminergic degeneration in Parkinson's disease models.

Su J1,2, Huang P3, Qin M1, Lu Q1,2, Sang X1,2, Cai Y1,4, Wang Y5, Liu F6, Wu R7, Wang X7, Jiang X6, Wang J5, Sun Q1,4, Chen S8, Xu J9.

Author information

1
Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
2
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
3
Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
4
CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
5
Department of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
6
Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
7
Department of Neurology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
8
Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. chen_sd@medmail.com.cn.
9
Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China. jin.xu@ion.ac.cn.

Abstract

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.

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