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, and their interaction was enhanced under MPP+ treatment. In contrast, STI-571 abrogated phosphorylation of GSK3β-Tyr216 induced by MPP+ in SN4741 cells and in primary midbrain neurons. Taken together, these results demonstrate that GSK3β is a novel c-Abl substrate, and c-Abl-GSk3β pathway mediates MPP+-induced ALP defects and neuronal cell death, which may represent a potential therapeutic target for PD.