Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra

Michael Francis Salvatore, Jin Lu Zhang, Delia M. Large, Patsy E. Wilson, Clelland R. Gash, Theresa Currier Thomas, John W. Haycock, Guoying Bing, John A. Stanford, Don M. Gash, Greg A. Gerhardt

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Abstract

Glial cell line-derived neurotrophic factor (GDNF) improves motor dysfunction associated with aging in rats and non-human primates, in animal models of Parkinson's disease, and may improve motoric function in patients with advanced Parkinson's disease. These improvements are associated with increased dopamine function in the nigrostriatal system, but the molecular events associated with this increase are unknown. In these studies, 100 μg of GDNF was injected into the striatum of normal aged (24-month-old) male Fischer 344 rats. The protein levels and phosphorylation of TH, ERK1/2, and related proteins were determined by blot-immunolabeling of striatum and substantia nigra harvested 30 days after injection. In GDNF-treated rats, TH phosphorylation at Ser31 increased ∼-40% in striatum and ∼250% in the substantia nigra. In the substantia nigra, there was a significant increase in ERK1 phosphorylation. In striatum, there was a significant increase in ERK2 phosphorylation. Microdialysis studies in striatum showed that both amphetamine- and potassium-evoked dopamine release in GDNF recipients were significantly increased. These data show that GDNF-induced increases in dopamine function are associated with a sustained increase in TH phosphorylation at Ser31 which is greatest in the substantia nigra and maintained for at least one month following a single striatal administration of GDNF. These findings, taken from the nigrostriatal system of normal aged rats, may help explain the long lasting effects of GDNF on dopamine function and prior studies supporting that a major effect of GDNF involves its effects on dopamine storage and somatodendritic release of dopamine in the substantia nigra.

Original languageEnglish
Pages (from-to)245-254
Number of pages10
JournalJournal of Neurochemistry
Volume90
Issue number1
DOIs
StatePublished - 1 Jul 2004

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Glial Cell Line-Derived Neurotrophic Factor
Corpus Striatum
Phosphorylation
Tyrosine 3-Monooxygenase
Substantia Nigra
Rats
Dopamine
Parkinson Disease
Inbred F344 Rats
Microdialysis
Amphetamine
Primates
Potassium
Proteins
Animal Models
Animals
Aging of materials
Injections

Keywords

  • Aging
  • Dopamine
  • ERK
  • MEK
  • Parkinson's disease

Cite this

Salvatore, Michael Francis ; Zhang, Jin Lu ; Large, Delia M. ; Wilson, Patsy E. ; Gash, Clelland R. ; Thomas, Theresa Currier ; Haycock, John W. ; Bing, Guoying ; Stanford, John A. ; Gash, Don M. ; Gerhardt, Greg A. / Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra. In: Journal of Neurochemistry. 2004 ; Vol. 90, No. 1. pp. 245-254.
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abstract = "Glial cell line-derived neurotrophic factor (GDNF) improves motor dysfunction associated with aging in rats and non-human primates, in animal models of Parkinson's disease, and may improve motoric function in patients with advanced Parkinson's disease. These improvements are associated with increased dopamine function in the nigrostriatal system, but the molecular events associated with this increase are unknown. In these studies, 100 μg of GDNF was injected into the striatum of normal aged (24-month-old) male Fischer 344 rats. The protein levels and phosphorylation of TH, ERK1/2, and related proteins were determined by blot-immunolabeling of striatum and substantia nigra harvested 30 days after injection. In GDNF-treated rats, TH phosphorylation at Ser31 increased ∼-40{\%} in striatum and ∼250{\%} in the substantia nigra. In the substantia nigra, there was a significant increase in ERK1 phosphorylation. In striatum, there was a significant increase in ERK2 phosphorylation. Microdialysis studies in striatum showed that both amphetamine- and potassium-evoked dopamine release in GDNF recipients were significantly increased. These data show that GDNF-induced increases in dopamine function are associated with a sustained increase in TH phosphorylation at Ser31 which is greatest in the substantia nigra and maintained for at least one month following a single striatal administration of GDNF. These findings, taken from the nigrostriatal system of normal aged rats, may help explain the long lasting effects of GDNF on dopamine function and prior studies supporting that a major effect of GDNF involves its effects on dopamine storage and somatodendritic release of dopamine in the substantia nigra.",
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Salvatore, MF, Zhang, JL, Large, DM, Wilson, PE, Gash, CR, Thomas, TC, Haycock, JW, Bing, G, Stanford, JA, Gash, DM & Gerhardt, GA 2004, 'Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra', Journal of Neurochemistry, vol. 90, no. 1, pp. 245-254. https://doi.org/10.1111/j.1471-4159.2004.02496.x

Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra. / Salvatore, Michael Francis; Zhang, Jin Lu; Large, Delia M.; Wilson, Patsy E.; Gash, Clelland R.; Thomas, Theresa Currier; Haycock, John W.; Bing, Guoying; Stanford, John A.; Gash, Don M.; Gerhardt, Greg A.

In: Journal of Neurochemistry, Vol. 90, No. 1, 01.07.2004, p. 245-254.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Salvatore, Michael Francis

AU - Zhang, Jin Lu

AU - Large, Delia M.

AU - Wilson, Patsy E.

AU - Gash, Clelland R.

AU - Thomas, Theresa Currier

AU - Haycock, John W.

AU - Bing, Guoying

AU - Stanford, John A.

AU - Gash, Don M.

AU - Gerhardt, Greg A.

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