| First Author | Li J | Year | 2020 |
| Journal | Front Mol Neurosci | Volume | 13 |
| Pages | 81 | PubMed ID | 32581704 |
| Mgi Jnum | J:294791 | Mgi Id | MGI:6445360 |
| Doi | 10.3389/fnmol.2020.00081 | Citation | Li J, et al. (2020) GSK-3beta Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib. Front Mol Neurosci 13:81 |
| abstractText | 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-3alpha and GSK-3beta, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3beta on PD pathogenesis, while the role of GSK-3alpha has been largely overlooked. Here, we report in situ observations that both GSK-3alpha and GSK-3beta 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-3alpha and GSK-3beta display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3a null (Gsk3a (DeltaDat) ) and Gsk3b null (Gsk3b (DeltaDat) ) mice, respectively. We found that Gsk3b (DeltaDat) , but not Gsk3a (DeltaDat) , showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3alpha and GSK-3beta 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-3beta and not GSK-3alpha is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3beta acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy. |
