Role of c-Abl-GSK3β Signaling in MPP+-Induced Autophagy-Lysosomal Dysfunction

Toxicological Sciences : an Official Journal of the Society of Toxicology
Yixian RenWenjun Li

Abstract

Impairment in autophagy-lysosomal pathway (ALP) results in accumulation of misfolded proteins and dysfunctional organelles, which is the hallmark of neurodegenerative diseases including Parkinson's disease (PD). Recent studies revealed activated nonreceptor tyrosine kinase Abelson (c-Abl) in PD models and brain specimen of PD patients. Inhibition of c-Abl through pharmacological inhibitors has been shown to enhance ALP function and provide neuroprotective effects in cells and animal models of PD. However, the molecular mechanisms of neuroprotective effects underlying c-Abl inhibition remain elusive. In this study, STI-571, a c-Abl inhibitor, rescued the ALP function through facilitating the nuclear translocation of TFEB and protected against MPP+-induced neuronal cell death. Furthermore, siRNA-mediated knock-down or pharmacological inhibition of GSK3β mitigated the MPP+-induced neuronal cell death, which was achieved through promoting TFEB nuclear localization and subsequently reversing the function of ALP. Intriguingly, either DPH, c-Abl activator, or MPP+ led to the activation of GSK3β, which is a negative regulator of TFEB. In addition, c-Abl directly interacted with GSK3β and catalyzed its phosphorylation at tyrosine 216, a...Continue Reading

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Citations

Apr 18, 2020·Molecular Neurodegeneration·Md Razaul KarimMichael K Lee
Feb 20, 2020·Environmental Science and Pollution Research International·Abdelmagid M ElmatbolyMohamed M Abdel-Daim
Jun 13, 2020·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Liuna YangJialong Chen
Aug 7, 2019·ACS Chemical Neuroscience·Pathik ParekhAmit Khairnar

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