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Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned nigrostriatal dopamine neurons induced by long-lasting overexpression of glial cell line derived neurotrophic factor in the striatum by lentiviral gene transfer.

Georgievska, Biljana LU ; Kirik, Deniz LU and Björklund, Anders LU (2002) In Experimental Neurology 177(2). p.461-474
Abstract
The effects of sustained (up to 9 months) striatal overexpression of glial cell line derived neurotrophic factor (GDNF) on lesioned nigrostriatal dopamine (DA) neurons was studied using a recombinant lentiviral (rLV) vector to deliver GDNF into the striatum 4 weeks prior to the creation of an intrastriatal 6-hydroxydopamine lesion. The results of the amphetamine-induced rotation suggested an initial partial protection followed by a complete recovery, whereas the spontaneous motor behaviors remained impaired. There was a clear protection of the nigral tyrosine hydroxylase (TH)-positive neurons in the rLV-GDNF group compared to rats injected with the control vector encoding green fluorescent protein (GFP) (70 and 20% of the intact side,... (More)
The effects of sustained (up to 9 months) striatal overexpression of glial cell line derived neurotrophic factor (GDNF) on lesioned nigrostriatal dopamine (DA) neurons was studied using a recombinant lentiviral (rLV) vector to deliver GDNF into the striatum 4 weeks prior to the creation of an intrastriatal 6-hydroxydopamine lesion. The results of the amphetamine-induced rotation suggested an initial partial protection followed by a complete recovery, whereas the spontaneous motor behaviors remained impaired. There was a clear protection of the nigral tyrosine hydroxylase (TH)-positive neurons in the rLV-GDNF group compared to rats injected with the control vector encoding green fluorescent protein (GFP) (70 and 20% of the intact side, respectively). However, the striatal TH+ fiber density was equally reduced (to 20% of the intact side) in both groups. Further morphological analyses indicated that the nigrostriatal projections of the DA neurons were indeed preserved in the GDNF group. The axonal projections were visualized using two independent methods: First, retrograde labeling of the nigral cell bodies by intrastriatal Fluoro-Gold injections showed that the majority of rescued cells in the GDNF group had preserved axonal projections to striatum. Second, injections of a recombinant adeno-associated viral vector expressing GFP into the nigra was used to anterogradely fill the DA neurons and their projections with GFP protein. GFP immunostaining clearly demonstrated that the fibers of the nigral DA cells were preserved along the nigrostriatal pathway and innervated large parts of the striatum, but did not express TH at detectable levels. In addition, fiber sprouting was observed in the globus pallidus, entopeduncular nucleus, and substantia nigra, corresponding to areas where GDNF protein was released. The lack of functional recovery in the spontaneous motor behaviors may, at least in part, be explained by this extensive aberrant fiber sprouting in the downstream striatal target nuclei and/or decreased synthesis of dopamine in the striatum. (Less)
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Neural Pathways: drug effects, Lentivirus: genetics, Luminescent Proteins: biosynthesis, Luminescent Proteins: genetics, Motor Activity: drug effects, Nerve Growth Factors: biosynthesis, Nerve Growth Factors: genetics, Nerve Growth Factors: pharmacology, Time, Tyrosine 3-Monooxygenase: deficiency, Tyrosine 3-Monooxygenase: metabolism, Horizontal, Substantia Nigra: pathology, Recovery of Function: genetics, Substantia Nigra: enzymology, Recovery of Function: drug effects, Sprague-Dawley, Neural Pathways: enzymology, Neural Pathways: pathology, Oxidopamine, Parkinsonian Disorders: chemically induced, Parkinsonian Disorders: physiopathology, Rats, Animal, Down-Regulation, Female, Gene Transfer, Animal: drug effects, Cell Count, Corpus Striatum: enzymology, Corpus Striatum: pathology, Disease Models, enzymology, Axons: pathology, Behavior, drug effects, Axons
in
Experimental Neurology
volume
177
issue
2
pages
461 - 474
publisher
Academic Press
external identifiers
  • wos:000179085500011
  • pmid:12429192
  • scopus:0036434879
ISSN
0014-4886
DOI
10.1006/exnr.2002.8006
language
English
LU publication?
yes
id
82d7679f-cc72-487b-99c4-d30b9825dad7 (old id 111209)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12429192&dopt=Abstract
date added to LUP
2007-07-12 13:25:14
date last changed
2017-11-19 03:28:49
@article{82d7679f-cc72-487b-99c4-d30b9825dad7,
  abstract     = {The effects of sustained (up to 9 months) striatal overexpression of glial cell line derived neurotrophic factor (GDNF) on lesioned nigrostriatal dopamine (DA) neurons was studied using a recombinant lentiviral (rLV) vector to deliver GDNF into the striatum 4 weeks prior to the creation of an intrastriatal 6-hydroxydopamine lesion. The results of the amphetamine-induced rotation suggested an initial partial protection followed by a complete recovery, whereas the spontaneous motor behaviors remained impaired. There was a clear protection of the nigral tyrosine hydroxylase (TH)-positive neurons in the rLV-GDNF group compared to rats injected with the control vector encoding green fluorescent protein (GFP) (70 and 20% of the intact side, respectively). However, the striatal TH+ fiber density was equally reduced (to 20% of the intact side) in both groups. Further morphological analyses indicated that the nigrostriatal projections of the DA neurons were indeed preserved in the GDNF group. The axonal projections were visualized using two independent methods: First, retrograde labeling of the nigral cell bodies by intrastriatal Fluoro-Gold injections showed that the majority of rescued cells in the GDNF group had preserved axonal projections to striatum. Second, injections of a recombinant adeno-associated viral vector expressing GFP into the nigra was used to anterogradely fill the DA neurons and their projections with GFP protein. GFP immunostaining clearly demonstrated that the fibers of the nigral DA cells were preserved along the nigrostriatal pathway and innervated large parts of the striatum, but did not express TH at detectable levels. In addition, fiber sprouting was observed in the globus pallidus, entopeduncular nucleus, and substantia nigra, corresponding to areas where GDNF protein was released. The lack of functional recovery in the spontaneous motor behaviors may, at least in part, be explained by this extensive aberrant fiber sprouting in the downstream striatal target nuclei and/or decreased synthesis of dopamine in the striatum.},
  author       = {Georgievska, Biljana and Kirik, Deniz and Björklund, Anders},
  issn         = {0014-4886},
  keyword      = {Neural Pathways: drug effects,Lentivirus: genetics,Luminescent Proteins: biosynthesis,Luminescent Proteins: genetics,Motor Activity: drug effects,Nerve Growth Factors: biosynthesis,Nerve Growth Factors: genetics,Nerve Growth Factors: pharmacology,Time,Tyrosine 3-Monooxygenase: deficiency,Tyrosine 3-Monooxygenase: metabolism,Horizontal,Substantia Nigra: pathology,Recovery of Function: genetics,Substantia Nigra: enzymology,Recovery of Function: drug effects,Sprague-Dawley,Neural Pathways: enzymology,Neural Pathways: pathology,Oxidopamine,Parkinsonian Disorders: chemically induced,Parkinsonian Disorders: physiopathology,Rats,Animal,Down-Regulation,Female,Gene Transfer,Animal: drug effects,Cell Count,Corpus Striatum: enzymology,Corpus Striatum: pathology,Disease Models,enzymology,Axons: pathology,Behavior,drug effects,Axons},
  language     = {eng},
  number       = {2},
  pages        = {461--474},
  publisher    = {Academic Press},
  series       = {Experimental Neurology},
  title        = {Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned nigrostriatal dopamine neurons induced by long-lasting overexpression of glial cell line derived neurotrophic factor in the striatum by lentiviral gene transfer.},
  url          = {http://dx.doi.org/10.1006/exnr.2002.8006},
  volume       = {177},
  year         = {2002},
}