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-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.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, whose major clinical symptoms include resting tremor, rigidity, and bradykinesia (Emamzadeh and Surguchov, 2018)
Our immunostaining results show that and phospho-GSK-3α Ser21 and phospho-glycogen synthesis kinase-3β (GSK-3β) Ser9 are weakly detected in surrounding glial cells, while they are apparent in the nigral dopaminergic neurons, which are similar to those shown in other studies (Roh et al, 2005; Endo et al, 2006; Li et al, 2007; Li N. et al, 2016; Gómez-Sintes and Lucas, 2010; Hurtado et al, 2012; Papazoglou et al, 2015; Wang et al, 2018; Kim et al, 2019), implying the abundance of phospho-GSK-3α Ser21 and phospho-GSK-3β Ser9 are much higher in neurons than those in glial cells
We demonstrated that GSK-3β but not GSK-3α contributes to nigral dopaminergic neurodegeneration
Summary
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, whose major clinical symptoms include resting tremor, rigidity, and bradykinesia (Emamzadeh and Surguchov, 2018). Striatal dopamine deficiency caused by the loss of nigral dopaminergic neurons is the main pathological feature of PD and responsible for the motor symptoms (Kalia and Lang, 2015). Expression of GSK-3β was found to be increased in the nigral pigmented neurons in postmortem PD brains (Nagao and Hayashi, 2009). For the first time, that pharmacological inhibition of GSK-3β exerted neuroprotective effects in a parkinsonian model (Wang et al, 2007). Another study using different PD animal models induced by either 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS) demonstrated that GSK-3β inhibition prevented dopaminergic neurodegeneration (Morales-Garcia et al, 2013). The detrimental effect of GSK3β activation on dopaminergic neuron survival was further demonstrated in transgenic mice expressing a constitutively active mutant of GSK-3β (Credle et al, 2015). Cell-type-specific roles of GSK-3β in nigral dopaminergic neurodegeneration have not been determined
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