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Long-term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system.

Rosenblad, Carl; Georgievska, Biljana LU and Kirik, Deniz LU (2003) In European Journal of Neuroscience 17(2). p.260-270
Abstract
Sustained neurotrophic factor treatment in neurodegenerative disorders such as Parkinson's disease is likely to affect both degenerating and intact neurons. To investigate the effect of long-term glial cell line-derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25-100-fold increase above control vector- or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by... (More)
Sustained neurotrophic factor treatment in neurodegenerative disorders such as Parkinson's disease is likely to affect both degenerating and intact neurons. To investigate the effect of long-term glial cell line-derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25-100-fold increase above control vector- or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by 39-72%) in the substantia nigra and ventral tegmental area neurons, and the optical density of tyrosine hydroxylase-immunoreactive innervation in the striatum was reduced by 25-52% with the most prominent reductions appearing caudally. No significant reduction was seen in striatal vesicular monoamine transporter 2-immunoreactivity or [3H]mazindole binding autoradiography to dopamine uptake sites, two other presynaptic markers in dopamine axon terminals. The striatal D1 and D2 receptor binding as determined by [3H]SCH23390 and [3H]spiperone binding, respectively, was unaltered relative to the intact side in both treatment groups. Preproenkephalin mRNA levels in postsynaptic striatal neurons, which increase upon removal of striatal dopamine, were also unaffected by the GDNF treatment. Taken together our findings indicate that sustained GDNF administration to intact nigrostriatal dopamine neurons selectively reduces tyrosine hydroxylase expression, without altering striatal dopamine transmission to the extent that compensatory changes in several other components related to dopamine storage and signalling occur. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
European Journal of Neuroscience
volume
17
issue
2
pages
260 - 270
publisher
Wiley-Blackwell
external identifiers
  • wos:000180571900008
  • pmid:12542662
  • scopus:0037267170
ISSN
1460-9568
DOI
10.1046/j.1460-9568.2003.02456.x
language
English
LU publication?
yes
id
0234a3f0-6e3a-4f15-af9e-6fd4fa2f6e6c (old id 111889)
date added to LUP
2007-07-19 09:28:22
date last changed
2018-01-07 05:33:50
@article{0234a3f0-6e3a-4f15-af9e-6fd4fa2f6e6c,
  abstract     = {Sustained neurotrophic factor treatment in neurodegenerative disorders such as Parkinson's disease is likely to affect both degenerating and intact neurons. To investigate the effect of long-term glial cell line-derived neurotrophic factor (GDNF) overexpression on intact nigrostriatal dopamine neurons, we injected a recombinant lentiviral vector encoding GDNF, or green fluorescent protein, in the right striatum of young adult rats. Thirteen months after viral injection GDNF levels were 4.5 ng/mg tissue in the striatum and 0.9 ng/mg in the substantia nigra as measured by ELISA, representing a 25-100-fold increase above control vector- or nontransduced tissue. GDNF overexpression significantly reduced tyrosine hydroxylase mRNA levels (by 39-72%) in the substantia nigra and ventral tegmental area neurons, and the optical density of tyrosine hydroxylase-immunoreactive innervation in the striatum was reduced by 25-52% with the most prominent reductions appearing caudally. No significant reduction was seen in striatal vesicular monoamine transporter 2-immunoreactivity or [3H]mazindole binding autoradiography to dopamine uptake sites, two other presynaptic markers in dopamine axon terminals. The striatal D1 and D2 receptor binding as determined by [3H]SCH23390 and [3H]spiperone binding, respectively, was unaltered relative to the intact side in both treatment groups. Preproenkephalin mRNA levels in postsynaptic striatal neurons, which increase upon removal of striatal dopamine, were also unaffected by the GDNF treatment. Taken together our findings indicate that sustained GDNF administration to intact nigrostriatal dopamine neurons selectively reduces tyrosine hydroxylase expression, without altering striatal dopamine transmission to the extent that compensatory changes in several other components related to dopamine storage and signalling occur.},
  author       = {Rosenblad, Carl and Georgievska, Biljana and Kirik, Deniz},
  issn         = {1460-9568},
  language     = {eng},
  number       = {2},
  pages        = {260--270},
  publisher    = {Wiley-Blackwell},
  series       = {European Journal of Neuroscience},
  title        = {Long-term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system.},
  url          = {http://dx.doi.org/10.1046/j.1460-9568.2003.02456.x},
  volume       = {17},
  year         = {2003},
}