GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib
Glycogen synthase kinase-3 (GSK-3) dysregulation has been implicated in nigral dopaminergic neurodegeneration, one of the main pathological features of Parkinson’s disease (PD). The two isoforms, GSK-3α and GSK-3β, have both been suggested to play a detrimental role in neuronal death. To date, sever...
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2020.00081/full |
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| author | Junyu Li Junyu Li Shanshan Ma Shanshan Ma Jingnan Chen Kunhua Hu Kunhua Hu Yongyi Li Yongyi Li Zeyu Zhang Zeyu Zhang Zixiang Su Zixiang Su James R. Woodgett Mingtao Li Mingtao Li Qiaoying Huang Qiaoying Huang |
| author_facet | Junyu Li Junyu Li Shanshan Ma Shanshan Ma Jingnan Chen Kunhua Hu Kunhua Hu Yongyi Li Yongyi Li Zeyu Zhang Zeyu Zhang Zixiang Su Zixiang Su James R. Woodgett Mingtao Li Mingtao Li Qiaoying Huang Qiaoying Huang |
| author_sort | Junyu Li |
| collection | DOAJ |
| description | Glycogen synthase kinase-3 (GSK-3) dysregulation has been implicated in nigral dopaminergic neurodegeneration, one of the main pathological features of Parkinson’s disease (PD). The two isoforms, GSK-3α and GSK-3β, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3β on PD pathogenesis, while the role of GSK-3α has been largely overlooked. Here, we report in situ observations that both GSK-3α and GSK-3β are dephosphorylated at a negatively acting regulatory serine, indicating kinase activation, selectively in nigral dopaminergic neurons following exposure of mice to 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP). To identify whether GSK-3α and GSK-3β display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3a null (Gsk3aΔDat) and Gsk3b null (Gsk3bΔDat) mice, respectively. We found that Gsk3bΔDat, but not Gsk3aΔDat, showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3α and GSK-3β in PD pathogenesis. In addition, we tested the neuroprotective effect of tideglusib, the most clinically advanced inhibitor of GSK-3, in the MPTP model of PD. Administration of higher doses (200 mg/kg and 500 mg/kg) of tideglusib exhibited significant neuroprotection, whereas 50 mg/kg tideglusib failed to prevent dopaminergic neurodegeneration from MPTP toxicity. Administration of 200 mg/kg tideglusib improved motor symptoms of MPTP-treated mice. Together, these data demonstrate GSK-3β and not GSK-3α is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3β acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy. |
| first_indexed | 2024-12-20T04:59:46Z |
| format | Article |
| id | doaj.art-06770337c211464ba5568809d7272a20 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-20T04:59:46Z |
| publishDate | 2020-06-01 |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-06770337c211464ba5568809d7272a202022-12-21T19:52:36ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992020-06-011310.3389/fnmol.2020.00081528775GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and TideglusibJunyu Li0Junyu Li1Shanshan Ma2Shanshan Ma3Jingnan Chen4Kunhua Hu5Kunhua Hu6Yongyi Li7Yongyi Li8Zeyu Zhang9Zeyu Zhang10Zixiang Su11Zixiang Su12James R. Woodgett13Mingtao Li14Mingtao Li15Qiaoying Huang16Qiaoying Huang17Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaZhixin High School, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, CanadaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGlycogen synthase kinase-3 (GSK-3) dysregulation has been implicated in nigral dopaminergic neurodegeneration, one of the main pathological features of Parkinson’s disease (PD). The two isoforms, GSK-3α and GSK-3β, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3β on PD pathogenesis, while the role of GSK-3α has been largely overlooked. Here, we report in situ observations that both GSK-3α and GSK-3β are dephosphorylated at a negatively acting regulatory serine, indicating kinase activation, selectively in nigral dopaminergic neurons following exposure of mice to 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP). To identify whether GSK-3α and GSK-3β display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3a null (Gsk3aΔDat) and Gsk3b null (Gsk3bΔDat) mice, respectively. We found that Gsk3bΔDat, but not Gsk3aΔDat, showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3α and GSK-3β in PD pathogenesis. In addition, we tested the neuroprotective effect of tideglusib, the most clinically advanced inhibitor of GSK-3, in the MPTP model of PD. Administration of higher doses (200 mg/kg and 500 mg/kg) of tideglusib exhibited significant neuroprotection, whereas 50 mg/kg tideglusib failed to prevent dopaminergic neurodegeneration from MPTP toxicity. Administration of 200 mg/kg tideglusib improved motor symptoms of MPTP-treated mice. Together, these data demonstrate GSK-3β and not GSK-3α is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3β acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy.https://www.frontiersin.org/article/10.3389/fnmol.2020.00081/fullParkinson’s diseaseGSK-3βGSK-3αtideglusibneuroprotectionMPTP |
| spellingShingle | Junyu Li Junyu Li Shanshan Ma Shanshan Ma Jingnan Chen Kunhua Hu Kunhua Hu Yongyi Li Yongyi Li Zeyu Zhang Zeyu Zhang Zixiang Su Zixiang Su James R. Woodgett Mingtao Li Mingtao Li Qiaoying Huang Qiaoying Huang GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib Frontiers in Molecular Neuroscience Parkinson’s disease GSK-3β GSK-3α tideglusib neuroprotection MPTP |
| title | GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib |
| title_full | GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib |
| title_fullStr | GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib |
| title_full_unstemmed | GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib |
| title_short | GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib |
| title_sort | gsk 3β contributes to parkinsonian dopaminergic neuron death evidence from conditional knockout mice and tideglusib |
| topic | Parkinson’s disease GSK-3β GSK-3α tideglusib neuroprotection MPTP |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2020.00081/full |
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