QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, July 21, 2004, 24(29):6437-6445; doi:10.1523/JNEUROSCI.1122-04.2004

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (32) Citing Articles via Google Scholar Google Scholar Articles by Georgievska, B. Articles by Björklund, A. Search for Related Content PubMed PubMed Citation Articles by Georgievska, B. Articles by Björklund, A.

 Previous Article  |  Next Article 

Development/Plasticity/Repair
Overexpression of Glial Cell Line-Derived Neurotrophic Factor Using a Lentiviral Vector Induces Time- and Dose-Dependent Downregulation of Tyrosine Hydroxylase in the Intact Nigrostriatal Dopamine System

Biljana Georgievska, Deniz Kirik, and Anders Björklund

Department of Physiological Sciences, Division of Neurobiology, Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden

The effects of continuous glial cell line-derived neurotrophic factor (GDNF) overexpression in the intact nigrostriatal dopamine (DA) system was studied using recombinant lentiviral (rLV) vector delivery of GDNF to the striatum or substantia nigra (SN) in the rat. Intrastriatal delivery of rLV-GDNF resulted in significant overexpression of GDNF in the striatum (2-4 ng/mg tissue) and anterograde transport of GDNF protein to the SN. Striatal rLV-GDNF delivery initially induced an increase in DA turnover (1-6 weeks), accompanied by significant contralateral turning in response to amphetamine, suggesting an enhancement of the DA system on the injected side. Starting 6 weeks after continuous GDNF delivery, we observed a selective downregulation of tyrosine hydroxylase (TH) protein (70%) that was maintained until the end of the experiment (24 weeks). A similar effect was observed when rLV-GDNF was injected into the SN. The magnitude of TH downregulation was related to the level of GDNF expression and was most pronounced in animals in which the striatal GDNF level exceeded 0.7 ng/mg tissue. The decreased TH protein levels were associated with similar reductions in the in vitro TH enzyme activity (70%); however, in vivo L-3,4-dihydroxyphenylalanine production rate and DA tissue levels were maintained at normal levels. The results indicate that downregulation of TH protein reflects a compensatory effect in response to continuous GDNF stimulation of the DA neurons mediated by a combination of overactivity at the DA synapse and a direct GDNF-induced action on TH gene expression. This compensatory mechanism is proposed to maintain long-term DA neuron function within the normal range.

Key words: dopamine; Parkinson; downregulation; gene therapy; glial cell line-derived neurotrophic factor; intact; overexpression; Parkinson's disease; tyrosine hydroxylase

---

Received Dec 2, 2003; revised May 27, 2004; accepted May 27, 2004.

This article has been cited by other articles:

				D.-Y. He and D. Ron Glial Cell Line-derived Neurotrophic Factor Reverses Ethanol-mediated Increases in Tyrosine Hydroxylase Immunoreactivity via Altering the Activity of Heat Shock Protein 90 J. Biol. Chem., May 9, 2008; 283(19): 12811 - 12818. [Abstract] [Full Text] [PDF]

				J. Mijatovic, M. Airavaara, A. Planken, P. Auvinen, A. Raasmaja, T. P. Piepponen, F. Costantini, L. Ahtee, and M. Saarma Constitutive Ret Activity in Knock-In Multiple Endocrine Neoplasia Type B Mice Induces Profound Elevation of Brain Dopamine Concentration via Enhanced Synthesis and Increases the Number of TH-Positive Cells in the Substantia Nigra J. Neurosci., May 2, 2007; 27(18): 4799 - 4809. [Abstract] [Full Text] [PDF]

				K. Cesnulevicius, M. Timmer, M. Wesemann, T. Thomas, T. Barkhausen, and C. Grothe Nucleofection Is the Most Efficient Nonviral Transfection Method for Neuronal Stem Cells Derived from Ventral Mesencephali with No Changes in Cell Composition or Dopaminergic Fate Stem Cells, December 1, 2006; 24(12): 2776 - 2791. [Abstract] [Full Text] [PDF]

				B. Dass, C. W. Olanow, and J. H. Kordower Gene transfer of trophic factors and stem cell grafting as treatments for Parkinson's disease Neurology, May 23, 2006; 66(10_suppl_4): S89 - S103. [Abstract] [Full Text]

				A. Eslamboli, B. Georgievska, R. M. Ridley, H. F. Baker, N. Muzyczka, C. Burger, R. J. Mandel, L. Annett, and D. Kirik Continuous Low-Level Glial Cell Line-Derived Neurotrophic Factor Delivery Using Recombinant Adeno-Associated Viral Vectors Provides Neuroprotection and Induces Behavioral Recovery in a Primate Model of Parkinson's Disease J. Neurosci., January 26, 2005; 25(4): 769 - 777. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help