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ORIGINAL RESEARCH ARTICLE

Multiple Molecular Pathways Are Involved in the Neuroprotection of GDNF Against Proteasome Inhibitor Induced Dopamine Neuron Degeneration In Vivo

Yunlan Du^*, Xuping Li, Dehua Yang, Xiaojie Zhang^*, Shen Chen^*, Kaixing Huang and Weidong Le^*,,1

^* Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China; Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai JiaoTong University School of Medicine, Shanghai 200025, China; and Department of Neurology, Baylor College of Medicine, Houston, Texas 77030

To whom requests for reprints should be addressed at ¹ Department of Neurology, Baylor College of Medicine, Houston, TX 77030. E-mail: weidongl{at}bcm.tmc.edu

The impairment of ubiquitin-proteasome system (UPS) is a cellular mechanism underlying the neurodegenerative process in Parkinson’s disease (PD). Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent neurotrophic factors promoting the growth and survival of mesencephalic dopamine (DA) neurons. To investigate whether GDNF has neuroprotective effects in a PD model induced by UPS impairment we administered GDNF by osmotic pump in C57BL/6 mice after nigrostriatal lesions with stereotactic injection of proteasome inhibitor lactacystin in the middle forebrain bundle. We found that lactacystin injection severely injured the nigral DA neurons and reduced the striatal levels of DA and its metabolites, while prolonged administration of GDNF at a sustained moderate dose for two weeks can significantly attenuate the lactacystin-induced loss of nigral DA neurons and striatal DA levels by 31% and 40%, respectively. We also investigated the molecular mechanisms for the neuroprotective effects of GDNF showing that lactacystin administration can cause the phosphorylation of extracellular signal-regulated kinase (ERK), p38MAPK (p38), and the c-Jun N-terminal kinase (JNK), whereas GDNF treatment can further enhance the phosphorylation of ERK and Akt but reduce the levels of JNK and p38. These results indicate that prolonged treatment with GDNF can protect the nigral DA neurons from the UPS impairment-induced degeneration. Several signaling path-ways including p38, JNK, Akt and ERK molecules seem to play an important role in this neuroprotection by GDNF.

Key Words: glial cell line-derived neurotrophic factor • proteasome inhibitor • mitogen-activated protein kinase • Parkinson’s disease