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Reduction of HIP2 expression causes motor function impairment and increased vulnerability to dopaminergic
Jinlin Su1,2, Pei Huang3, Meiling Qin1
1Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
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.
Insights
Huntingtin interaction protein 2 (HIP2) insufficiency contributes to Parkinson
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Huntingtin interaction protein 2 (HIP2) is an E2 ubiquitin-conjugating enzyme linked to neurodegenerative diseases.
- HIP2 mRNA is a potential blood biomarker for Parkinson's disease (PD), but its role in PD development and correlation with disease severity is unclear.
Purpose of the Study:
- To investigate if altered HIP2 expression contributes to Parkinson's disease pathogenesis.
- To determine if blood HIP2 levels reflect brain expression and motor function in PD patients.
- To validate HIP2 as a reversible biomarker for PD.
Main Methods:
- Established a mouse model with HIP2 haploinsufficiency.
- Utilized 6-hydroxydopamine (6-OHDA) and MPTP mouse models for PD.
- Analyzed HIP2 mRNA levels in brain and blood of mice and over 300 PD patients.
- Conducted a 1-year study on 20 PD patients undergoing Tai Chi training.
Main Results:
- HIP2 haploinsufficiency in mice caused motor impairment and dopaminergic neuronal loss.
- HIP2 deficiency exacerbated neurodegeneration in PD mouse models.
- Decreased HIP2 mRNA was observed concurrently in the brain and blood of MPTP-treated mice and in PD patients.
- Blood HIP2 mRNA levels reversed and correlated with improved motor function in PD patients practicing Tai Chi.
Conclusions:
- HIP2 insufficiency is a contributing factor to Parkinson's disease.
- Blood HIP2 mRNA is a validated, reversible biomarker for PD, reflecting disease status and response to intervention.