Expression of Concern: Glycogen synthase kinase 3β (GSK3β) mediates 6‐ hydroxydopamine‐induced neuronal death

Abstract

The causes of sporadic Parkinson's disease (PD) are poorly understood. 6‐Hydroxydopamine (6‐ OHDA), a PD mimetic, is widely used to model this neurodegenerative disorder in vitro and in vivo; however, the underlying mechanisms remain incompletely elucidated. We demonstrate here that 6‐ OHDA evoked endoplasmic reticulum (ER) stress, which was characterized by an up‐regulation in the expression of GRP78 and GADD153 (Chop), cleavage of procaspase‐12, and phosphorylation of eukaryotic initiation factor‐2 a in a human dopaminergic neuronal cell line (SH‐SY5Y) and cultured rat cerebellar granule neurons (CGNs). Glycogen synthase kinase‐3 β (GSK3β) responds to ER stress, and its activity is regulated by phosphorylation. 6‐OHDA significantly inhibited phosphorylation of GSK3β at Ser9, whereas it induced hyperphosphorylation of Tyr216 with little effect on GSK3β expression in SH‐SY5Y cells and PC12 cells (a rat dopamine cell line), as well as CGNs. Furthermore, 6‐OHDA decreased the expression of cyclin D1, a substrate of GSK3β, and dephosphorylated Akt, the upstream signaling component of GSK3β. Protein phosphatase 2A (PP2A), an ER stress‐responsive phosphatase, was involved in 6‐OHDA‐induced GSK3β dephosphorylation (Ser9). Blocking GSK3β activity by selective inhibitors (lithium, TDZD‐8, and L803‐mts) prevented 6‐OHDA‐induced cleavage of caspase‐3 and poly(ADP‐ribose) polymerase (PARP), DNA fragmentations and cell death. With a tetracycline (Tet)‐controlled TrkB inducible system, we demonstrated that activation of TrkB in SH‐ SY5Y cells alleviated 6‐OHDA‐induced GSK3β dephosphorylation (Ser9) and ameliorated 6‐OHDA neurotoxicity. TrkB activation also protected CGNs against 6‐OHDA‐induced damage. Although antioxidants also offered neuroprotection, they had little effect on 6‐OHDA‐induced GSK3β activation. These results suggest that GSK3β is a critical intermediate in pro‐apoptotic signaling cascades that are associated with neurodegenerative diseases, thus providing a potential target site amenable to pharmacological intervention.