Reduction of HIP2 expression causes motor function impairment and increased vulnerability to dopaminergic degeneration in Parkinson\u2019s disease models

Jinlin Su,Rong Wu,Shengdi Chen,Xiaoping Wang,Pei Huang,Yijun Cai,Xiaoxing Jiang,Fubing Liu,Ying Wang,Meiling Qin,Jian Wang,Qiang Sun,Xiao Sang,Qingqing Lu,Jin Xu

doi:10.1038/s41419-018-1066-z

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.

Highlights

Huntingtin interaction protein 2 (HIP2), known as UBE2K or E2-25K, was identified as an E2 ubiquitin-Official journal of the Cell Death Differentiation AssociationSu et al Cell Death and Disease (2018)9:1020inhibition of caspase-12 expression and activation[6]
Our results indicated that decreased HIP2 expression increased the dopaminergic vulnerability in the 6-OHDA model for Parkinson’s disease (PD), and the reduced blood HIP2 faithfully reflected the similar changes in the brain
In this study, by using various in vivo models, we have demonstrated that reduced HIP2 expression contributed to dopaminergic neuronal loss and motor deficits

Summary

Introduction

Inhibition of caspase-12 expression and activation[6] These studies provided us with some evidence to support the potential roles of HIP2 in various neurodegenerative diseases, the roles of HIP2 in neurodegeneration in vivo have not been well characterized. Sufficient evidence has validated the association between HIP2 and PD, it is unclear how the change 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. It is unclear whether the HIP2 expression in the blood could change with therapeutic intervention

Methods

Results

Conclusion