GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib
Open accessAbstract
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 (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-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.
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The beneficial effect of FMT on neuroinflammation is ascribed to GM modulating microglia and astrocyte activation in SN by regulating the TLR4/NF-κB pathway and reducing expression of GSK3β, iNOS and IL-1β.
“This beneficial effect should be ascribed to the ability of GM to modulate microglia and astrocyte activation in SN by regulating the TLR4/NF-κB pro-inflammatory pathway and reducing the expression of GSK3β, iNOS and IL-1β, which are implicated in PD pathogenesis and progression [469,470,471,472,478,479,480].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [479]
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- Authors
- Li, J., Ma, S., Chen, J., Hu, K., Li, Y., Zhang, Z., Su, Z., Woodgett, J. R., Li, M., & Huang, Q.
- Affiliations
- Sun Yat-sen University (CN)
- Lunenfeld-Tanenbaum Research Institute (CA)
- Corresponding author
- Li, Mingtao
- Huang, Qiaoying
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2020-06-03
- Volume
- 13
- Pages
- 81-81
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC7283909
- OpenAlex
- W3033352229
- Cited by
- 76
- References
- 83
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 15 · 2023: 12 · 2022: 15 · 2021: 6
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (U180168, 81771368, 81771368, 81601104)
- Natural Science Foundation of Guangdong Province (2017A030313507, 2017A030313862)
- Guangzhou Municipal Science and Technology Project (201704020066, 201804020008, 201803040020)
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- GSK3β, GSK3α, Parkinson's disease, dopaminergic neuron death, substantia nigra, MPTP, tideglusib, GSK-3 inhibitors, conditional knockout mice, kinase dephosphorylation, functional redundancy, neuroprotection, motor symptoms
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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