Long-term glial cell line-derived neurotrophic factor overexpression in the intact nigrostriatal system in rats leads to a decrease of dopamine and increase of tetrahydrobiopterin production
Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic system. Brain delivery of glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore the dopaminergic pathway in various animal models of PD. However, GDNF overexpression in the dopaminergic pathway leads to a time-dependent down-regulation of tyrosine hydroxylase (TH), a key enzyme in dopamine synthesis. In order to elucidate GDNF-mediated biochemical effects on dopaminergic neurons, we overexpressed GDNF in the intact rat striatum using a lentiviral vector-mediated gene transfer technique. Long-term GDNF overexpression led to increased GTP cyclohydrolase I (GTPCH I) activity and tetrahydrobiopterin (BH4) levels. Further, we observed a down-regulation of TH enzyme activity in morphologically intact striatal dopaminergic nerve terminals, as well as a significant decrease of dopamine levels in striatal tissue samples. These results indicate that long-term GDNF delivery is a major factor affecting dopamine biosynthesis via a direct or indirect modulation of TH and GTPCH I and further underscore the importance of assessing both GDNF dose and delivery duration prior to clinical application in order to circumvent potentially adverse pharmacological effects on the biosynthesis of dopamine.
Keywords: Animals ; Biopterin/ analogs & derivatives/biosynthesis/ metabolism ; Corpus Striatum/drug effects/ metabolism/pathology/physiopathology ; Disease Models ; Animal ; Dopamine/ metabolism ; Dose-Response Relationship ; Drug ; Down-Regulation/genetics ; Female ; GTP Cyclohydrolase/metabolism ; Gene Expression Regulation/physiology ; Gene Transfer Techniques ; Genetic Vectors ; Glial Cell Line-Derived Neurotrophic Factor ; Lentivirus/genetics ; Membrane Glycoproteins/metabolism ; Membrane Transport Proteins/metabolism ; Nerve Growth Factors/ biosynthesis/genetics ; Neural Pathways/metabolism/physiopathology ; Parkinson Disease/drug therapy/ metabolism/pathology ; Presynaptic Terminals/drug effects/metabolism ; Rats ; Rats ; Sprague-Dawley ; Substantia Nigra/drug effects/ metabolism/pathology ; Tyrosine 3-Monooxygenase/metabolism ; Vesicular Biogenic Amine Transport Proteins ; Animal ; Rats
Ecole Polytechnique Federale de Lausanne, EPFL, Integrative Biosciences Institute, Lausanne, Switzerland.
Record created on 2007-03-09, modified on 2016-08-08