Mitochondrial dysfunction and apoptosis are attenuated through activation of AMPK/GSK-3β/PP2A pathway in Parkinson's disease

Parkinson's disease (PD) is a common neurological disorder worldwide, characterized by loss of dopaminergic neurons and decrease of dopamine content. Mitochondria plays an important role in the development of PD. Adenosine 5'-monophosphate-activated protein kinase (AMPK), glycogen synthase kinase 3 (GSK-3 beta) and protein phosphatase 2A (PP2A) are all key proteins that regulate mitochondrial metabolism and apoptosis, and they are involved in a variety of neurodegenerative diseases. Here, we aimed to explore the involvement of mitochondrial dysfunction and apoptosis in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP)-induced PD mice and MPP+ iodide-induced PC12 cells. MPTP-induced mice were subjected to behavioral testing to assess PD-like behaviors. Various molecular biological techniques including ELISA, Western blot, TUNEL assay, flow cytometry, and the important instruments Seahorse XF24 Extracellular and high performance liquid chromatography (HPLC), were used to identify the underlying molecular events of mitochondria. Treatment with the AMPK activator GSK621 dramatically ameliorated PD by increasing the levels of dopamine and rescuing the loss of dopaminergic neurons, which is dependent on the mitochondrial pathway. Moreover, regulation of AMPK/GSK-3 beta/PP2A pathway-related proteins by GSK621 was partially inhibited the development of PD, suggesting a negative feedback loop exists between AMPK action and mitochondrial dysfunction-mediated apoptosis. Our data preliminarily indicated that mitochondrial dysfunction and apoptosis in the pathogenesis of PD might be mediated by AMPK/GSK-3 beta/PP2A pathway action, which might be a promising new option for future therapy of PD.