2. Academic Validation
  3. Ucf-101 protects in vivoandin vitro models of PD against 6-hydroxydopamine toxicity by alleviating endoplasmic reticulum stress via the Wnt/β-catenin pathway

Ucf-101 protects in vivoandin vitro models of PD against 6-hydroxydopamine toxicity by alleviating endoplasmic reticulum stress via the Wnt/β-catenin pathway

  • J Clin Neurosci. 2020 Jan;71:217-225. doi: 10.1016/j.jocn.2019.11.023.
Yanxia Li 1,  Zhaoyang Liu 2,  Dan Wang 3,  Hua Gao 4,  Zhengquan Zhu 5,  Yuling Wang 6,  Qin Luo 7,  Sen Jiang 3,  Ji Zhang 8,  Xinling Yang 9
Affiliations

Affiliations

  • 1 Department of Rehabilitation Medicine, the Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
  • 2 Department of Stomatology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, China.
  • 3 Department of Neurology, the Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
  • 4 Department of Neurology, the Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
  • 5 Department of Neurosurgery, Affiliated Tumor Hospital of Xinjiang Medical, University, Xinshi District, Urumqi, China.
  • 6 Department of VIP, the first Affiliated Hospital of Xinjiang Medical University, Xinshi District, Urumqi, China.
  • 7 Department of VIP, Affiliated Tumor Hospital of Xinjiang Medical University, Xinshi District, Urumqi, China.
  • 8 Department of Neurosurgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address: zhangji@sysucc.org.cn.
  • 9 Department of Neurology, the Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China. Electronic address: yangxinling2014@163.com.
PMID: 31883812 DOI: 10.1016/j.jocn.2019.11.023
Abstract

The accumulation of α-syn which induce endoplasmic reticulum stress (ERS) and mediate various signaling pathways involved in DA neuronal degeneration, and the Apoptosis of dopamine (DA) neurons are pathological markers of Parkinson's disease (PD). High-temperature requirement protein A2 (HtrA2) is synthesized in the endoplasmic reticulum, and the expression level of HtrA2 can be upregulated by drugs or by unfolded proteins. Ucf-101 is a specific inhibitor of HtrA2, and studies have shown that Ucf-101 reduced Apoptosis in PC12 cells. Our study showed that PC12 cells treated with 60 μM 6-OHDA for 24 h had significantly decreased cell viability compared to that of controls. A low concentration (2.5 μM) of Ucf-101 decreased the Apoptosis rate of the PD cell model, but a high concentration (≥10 μM) increased the Apoptosis rate, compared to that of controls. 6-OHDA upregulated the expression of HtrA2, α-syn, CHOP, Grp78 and active Caspase-3 and reduced the levels of TH and XIAP. Ucf-101 reduced the level of ERS and Apoptosis bothin vivoandin vitro. The ratio of p-GSK3β (Tyr216 to Ser9) increased in PD rats. However, Ucf-101 down-regulated the activation of GSK3β and activated the Wnt/β-catenin pathway that was caused by 6-OHDA. Ucf-101 activated the Wnt/β-catenin pathway and significantly attenuated 6-OHDA-induced neurotoxicity, which was related to the inhibition of ERS and the reduction of the Apoptosis rate of PC12 cells and DA neurons in the midbrain of PD rats. Ucf-101 has certain neuroprotective effects.

Keywords

Apoptosis; ERS; HtrA2 inhibitor; Parkinson’s disease; Ucf-101; Wnt/β-catenin.

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