Multiple molecular pathways are involved in the neuroprotection of GDNF against proteasome inhibitor induced dopamine neuron degeneration in vivo.
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.
Du
Yunlan
Y
Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
Li
Xuping
X
Yang
Dehua
D
Zhang
Xiaojie
X
Chen
Shen
S
Huang
Kaixing
K
Le
Weidong
W
D000111:Acetylcysteine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000627:therapeutic use*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D061988:Proteasome Inhibitors; C067713:lactacystin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D004298:Dopamine; D000111:Acetylcysteine