Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease

Abstract

Shanshan Hu, 1,* Meigui Hu, 2,* Jian Liu, 3 Bei Zhang, 4 Zhen Zhang, 5 Fiona H Zhou, 6 Liping Wang, 5, 6 Jianghui Dong 5, 6 1Good Clinical Practice Center, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou, People’s Republic of China; 2The Second School of Clinical Medicine, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong, People’s Republic of China; 3Department of Anatomy, Zunyi Medical University, Zunyi 563000, Guizhou, People’s Republic of China; 4Department of Stomatology, The First People’s Hospital of Zunyi, Zunyi 563099, Guizhou, People’s Republic of China; 5Department of Hand Surgery, Department of Plastic Reconstructive Surgery, Ningbo No. 6 Hospital, Ningbo 315040, People’s Republic of China; 6School of Pharmacy and Medical Sciences, and UniSA Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia*These authors contributed equally to this workCorrespondence: Jianghui Dong; Liping WangDepartment of Hand Surgery, Ningbo No. 6 Hospital, Ningbo 315040, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]; [email protected]: Parkinson’s disease (PD) is the second most common neurodegenerative disease. The α-Synuclein is a major component of Lewy bodies and Lewy neurites, the pathologic hallmark of PD. It is known that α-Synuclein is phosphorylated (p-α-Synuclein) in PD and tau-hyperphosphorylation (p-Tau) is also a pathologic feature of PD. However, the relationship between p-Synuclein and p-Tau in PD is not clear, in particular in the MPTP model of PD. The purpose of this study was to reveal their relationship in the mouse MPTP model.Methods: Firstly, the p-α-Synuclein, α-Synuclein, p-Tau and Tau protein levels were analyzed. Then, GSK3β activation was determined using immunoblot and immunohistochemical staining. Finally, the dopaminergic neurodegeneration was assessed using Tyrosine Hydroxylase (TH) staining and retrograde labeling and microglial marker were labeled. Microglial activation and nigrostriatal pathway degeneration were observed.Results: The results showed that p-α-Synuclein, α-Synuclein, p-Tau and Tau were upregulated in both hippocampus and substantia nigra of the PD mouse model. Furthermore, p-α-Synuclein and p-Tau were localized in the same regions of substantial nigra (SN) and dentate gyrus (DG) of hippocampus (Hippo). The activated form of GSK3β (phosphor GSK3β Y216) was increased in multiple brain areas. The GSK3β inhibitor AZD1080 injected in MPTP mice suppressed the expression of p-Tau and p-GSK3β and improved motor functions.Conclusion: These findings revealed that p-α-Synuclein and p-Tau proteins are key pathological events leading to neurodegeneration and motor dysfunctions in the mouse MPTP model of PD. Our data suggest that the interference with the GSK3β activity may be an effective approach for the treatment of PD.Keywords: α-Synuclein phosphorylation, Tau phosphorylation, Parkinson’s disease

Keywords

• α-synuclein phosphorylation
• tau phosphorylation
• parkinson’s disease