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Glial Cell-Derived Neurotrophic Factor Protects Against Proteasome Inhibition-Induced Dopamine Neuron Degeneration by Suppression of Endoplasmic Reticulum Stress and Caspase-3 Activation

¹ Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Institute of Neurology, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, China.
³ State Key Laboratory of Medical Genomics, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai, China.

Address correspondence to Weidong Le, MD, PhD, Institute of Neurology, Jiao Tong University School of Medicine, Shanghai, China. E-mail: wdle{at}sibs.ac.cn

Evidence has shown that ubiquitin proteasome system (UPS) impairment plays an important role in the dopamine (DA) neurodegeneration in Parkinson's disease (PD). It has been reported that application of proteasomal inhibitor lactacystin in ventral mesencephalon (VM) cultures can cause DA neurodegeneration, although the underlying mechanisms are not clear. Herein, we used the lactacystin-induced DA cell degeneration model to study the neuroprotection of glial cell-derived neurotrophic factor (GDNF) in VM cultures. We measured the expression of endoplasmic reticulum stress (ERS)-related genes, and determined the caspase-3 activation, apoptotic cell death, as well as -synuclein-positive inclusions in DA neurons. We found that GDNF treatment significantly suppressed the expression of ERS-related genes and inhibited the activation of caspase-3 and apoptotic cell death without affecting -synuclein-positive inclusions in DA neurons. Our study suggests that the protection of GDNF against DA neurodegeneration in the UPS impairment model is associated with ERS and caspase-3 suppression.