GSK-3? Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib.

ABSTRACT: 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-3? and GSK-3?, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3? on PD pathogenesis, while the role of GSK-3? has been largely overlooked. Here, we report in situ observations that both GSK-3? and GSK-3? 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-3? and GSK-3? display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3a null (Gsk3a ?Dat ) and Gsk3b null (Gsk3b ?Dat ) mice, respectively. We found that Gsk3b ?Dat , but not Gsk3a ?Dat , showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3? and GSK-3? 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-3? and not GSK-3? is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3? acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy.

SUBMITTER: Li J 

PROVIDER: S-EPMC7283909 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature