Molecular mechanism of the neurotrophic effect of GDNF on DA neurons: role of protein kinase CK2.
Glial cell line-derived neurotrophic factor (GDNF) is suggested as a specific neurotrophic factor for midbrain dopamine (DA) neurons, but the molecular mechanism underlying the neuroprotective action of GDNF is not well known. In the present study, we have shown that GDNF increased protein kinase CK2 activity in rat substantia nigra (SN) in a dose-dependent and time-dependent manner. This effect is prevented by prior treatment of the receptor Ret blocker K-252b. Immunostaining results also revealed that CK2 is expressed in TH-positive neurons in mesencephalon culture. Transfection of the wildtype CK2alpha DNA increased, whereas transfection of the catalytically inactive CK2alphaA156 mutant DNA decreased CK2 activity in the SN. CK2alphaA156 mutant DNA also antagonized the enhancing effect of GDNF on CK2 activity. It also antagonized the enhancing effects of GDNF on tyrosine hydroxylase (TH) protein level in the SN, DA turnover in the striatum and rotarod performance in rats. Further, CK2alpha wildtype DNA increased, whereas CK2alphaA156 mutant DNA decreased TH activity in the SN without altering the TH protein level. On the other hand, the DA neuron toxin 1-methyl-4-phenylpyridinium iodide (MPP+) markedly decreased the number of TH-positive neurons and TH protein level in the SN, decreased DA level in the striatum and impaired rotarod performance in rats. Over-expression of the CK2alpha wildtype DNA partially, but significantly, prevented the deteriorating effect of MPP+ on these measures. Prior administration of MPP+ also antagonized the enhancing effect of GDNF on CK2 activity. These results together suggest that the CK2 signaling pathway contributes to the neuroprotective action of GDNF on DA neurons.
Chao
Chih C
CC
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, ROC.
Chiang
Cheng H
CH
Ma
Yun L
YL
Lee
Eminy H Y
EH
D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage*; D008297:Male; D009043:Motor Activity; D009414:Nerve Growth Factors / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology*
D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D047390:Casein Kinase II; D004298:Dopamine