Title:Ablation of Shank1 Protects against 6-OHDA-induced Cytotoxicity via PRDX3-mediated Inhibition of ER Stress in SN4741 Cells
Volume: 23
Issue: 3
Author(s): Ye-Ping Xu, Jing Zhang, Xue Mei, Yan Wu, Wei Jiao, Yu-Hai Wang*Ai-Qin Zhang*
Affiliation:
- Department of Neurosurgery, Wuxi Taihu Hospital, Wuxi Clinical College of Anhui Medical University, Wuxi, Jiangsu 214044, China
- Department of Nursing, Jinling Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu 210000, China
Keywords:
Parkinson’s disease, shank1, ER stress, PRDX3, SN4741 cells, 6-OHDA, cytotoxicity.
Abstract:
Background: Postsynaptic density (PSD) is an electron-dense structure that contains various
scaffolding and signaling proteins. Shank1 is a master regulator of the synaptic scaffold located at
glutamatergic synapses, and has been proposed to be involved in multiple neurological disorders.
Methods: In this study, we investigated the role of shank1 in an in vitro Parkinson’s disease (PD)
model mimicked by 6-OHDA treatment in neuronal SN4741 cells. The expression of related molecules
was detected by western blot and immunostaining.
Results: We found that 6-OHDA significantly increased the mRNA and protein levels of shank1 in
SN4741 cells, but the subcellular distribution was not altered. Knockdown of shank1 via small interfering
RNA (siRNA) protected against 6-OHDA treatment, as evidenced by reduced lactate dehydrogenase
(LDH) release and decreased apoptosis. The results of RT-PCR and western blot showed that
knockdown of shank1 markedly inhibited the activation of endoplasmic reticulum (ER) stress associated
factors after 6-OHDA exposure. In addition, the downregulation of shank1 obviously increased
the expression of PRDX3, which was accompanied by the preservation of mitochondrial function.
Mechanically, downregulation of PRDX3 via siRNA partially prevented the shank1 knockdowninduced
protection against 6-OHDA in SN4741 cells.
Conclusion: In summary, the present study has provided the first evidence that the knockdown of
shank1 protects against 6-OHDA-induced ER stress and mitochondrial dysfunction through activating
the PRDX3 pathway.