Abstract
Post-stroke secondary brain damage is significantly influenced by the induction and accumulation of α-Synuclein (α-Syn). α-Syn-positive inclusions are often present in tauopathies and elevated tau levels and phosphorylation promotes neurodegeneration. Glycogen synthase kinase 3β (GSK-3β) is a known promoter of tau phosphorylation. We currently evaluated the interaction of α-Syn with GSK-3β and tau in post-ischemic mouse brain. Transient focal ischemia led to increased cerebral protein–protein interaction of α-Syn with both GSK-3β and tau and elevated tau phosphorylation. Treatment with a GSK-3β inhibitor prevented post-ischemic tau phosphorylation. Furthermore, α-Syn interaction was observed to be crucial for post-ischemic GSK-3β-dependent tau hyperphosphorylation as it was not seen in α-Syn knockout mice. Moreover, tau knockout mice show significantly smaller brain damage after transient focal ischemia. Overall, the present study indicates that GSK-3β catalyzes the α-Syn-dependent tau phosphorylation and preventing this interaction is crucial to limit post-ischemic secondary brain damage.
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Acknowledgements
Partially supported by NIH RO1 NS101960 and UW Department of Neurological Surgery. Dr. Vemuganti is the recipient of a Research Career Scientist award (# IK6BX005690) from the US Department of Veterans Affairs. We thank Mr. Shreyas Kumar for proofreading the text.
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National Institutes of Health, RO1 NS101960
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SLM, THK, BC, and RV contributed to the conception and design of the study; SLM, THK, and BC contributed to the acquisition and analysis of data; SLM, BC, and RV contributed to drafting the text.
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Mehta, S.L., Kim, T., Chelluboina, B. et al. Tau and GSK-3β are Critical Contributors to α-Synuclein-Mediated Post-Stroke Brain Damage. Neuromol Med 25, 94–101 (2023). https://doi.org/10.1007/s12017-022-08731-0
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DOI: https://doi.org/10.1007/s12017-022-08731-0