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A Model of GDNF Gene Therapy in Mice with 6-Hydroxydopamine Lesions: Time Course of Neurorestorative Effects and ERK1/2 Activation

Lindgren, Niklas LU ; Francardo, Veronica LU ; Quintino, Luis LU ; Lundberg, Cecilia LU and Cenci Nilsson, Angela LU (2012) In Journal of Parkinson's Disease 2(4). p.333-348
Abstract
Background: Glial cell line-derived neurotrophic factor (GDNF) is the most promising neurotrophin for restorative treatments in Parkinson's disease, but its biological effects are not completely understood. Objective: To define a model of GDNF gene therapy in the mouse, we studied the long-term effects of lentiviral GDNF delivery in mice with striatal 6-hydroxydopamine (6-OHDA) lesions. Methods: Lentiviral vectors coding for GDNF or green fluorescent protein (GFP) were injected unilaterally in the striatum two weeks prior to the 6-OHDA lesion. Mice were monitored on tests of spontaneous activity and amphetamine-induced rotation at 1, 4, 10 and 35 weeks post-lesion. Brains were processed immunohistochemically for tyrosine hydroxylase (TH)... (More)
Background: Glial cell line-derived neurotrophic factor (GDNF) is the most promising neurotrophin for restorative treatments in Parkinson's disease, but its biological effects are not completely understood. Objective: To define a model of GDNF gene therapy in the mouse, we studied the long-term effects of lentiviral GDNF delivery in mice with striatal 6-hydroxydopamine (6-OHDA) lesions. Methods: Lentiviral vectors coding for GDNF or green fluorescent protein (GFP) were injected unilaterally in the striatum two weeks prior to the 6-OHDA lesion. Mice were monitored on tests of spontaneous activity and amphetamine-induced rotation at 1, 4, 10 and 35 weeks post-lesion. Brains were processed immunohistochemically for tyrosine hydroxylase (TH) and markers of extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation at the same time points. Results: Lentiviral GDNF significantly inhibited both spontaneous and amphetamine-induced rotation. Compared to the control vector, lentiviral GDNF resulted in a partial protection of TH-positive cells in the substantia nigra, and in a nearly total restoration of striatal TH immunostaining by 35 weeks. A progressive sprouting of TH-positive neurites occurred in both the globus pallidus and the substantia nigra, reaching a 4-5 fold increase above controls by 35 weeks. This effect was paralleled by a long-term supranormal activation of ERK1/2 and its downstream target, phospho-Ser31 TH. Conclusions: Lentiviral GDNF delivery produced robust long-term signaling responses and neurorestoration. This experimental model of GDNF gene therapy will be particularly suitable to study the molecular mechanisms of dopaminergic fiber sprouting, a long-term response to GDNF delivery that also occurs in Parkinson's disease patients. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Neurotoxin, neuroprotection, rodent, mitogen-activated protein kinases, MAPK, trophic factor, GDNF
in
Journal of Parkinson's Disease
volume
2
issue
4
pages
333 - 348
publisher
IOS Press
external identifiers
  • wos:000314529900009
  • scopus:84874820297
ISSN
1877-718X
DOI
10.3233/JPD-012146
language
English
LU publication?
yes
id
5266c079-7303-4f41-a0d4-3b731105035e (old id 3577715)
date added to LUP
2013-04-02 07:44:15
date last changed
2017-11-19 03:07:12
@article{5266c079-7303-4f41-a0d4-3b731105035e,
  abstract     = {Background: Glial cell line-derived neurotrophic factor (GDNF) is the most promising neurotrophin for restorative treatments in Parkinson's disease, but its biological effects are not completely understood. Objective: To define a model of GDNF gene therapy in the mouse, we studied the long-term effects of lentiviral GDNF delivery in mice with striatal 6-hydroxydopamine (6-OHDA) lesions. Methods: Lentiviral vectors coding for GDNF or green fluorescent protein (GFP) were injected unilaterally in the striatum two weeks prior to the 6-OHDA lesion. Mice were monitored on tests of spontaneous activity and amphetamine-induced rotation at 1, 4, 10 and 35 weeks post-lesion. Brains were processed immunohistochemically for tyrosine hydroxylase (TH) and markers of extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation at the same time points. Results: Lentiviral GDNF significantly inhibited both spontaneous and amphetamine-induced rotation. Compared to the control vector, lentiviral GDNF resulted in a partial protection of TH-positive cells in the substantia nigra, and in a nearly total restoration of striatal TH immunostaining by 35 weeks. A progressive sprouting of TH-positive neurites occurred in both the globus pallidus and the substantia nigra, reaching a 4-5 fold increase above controls by 35 weeks. This effect was paralleled by a long-term supranormal activation of ERK1/2 and its downstream target, phospho-Ser31 TH. Conclusions: Lentiviral GDNF delivery produced robust long-term signaling responses and neurorestoration. This experimental model of GDNF gene therapy will be particularly suitable to study the molecular mechanisms of dopaminergic fiber sprouting, a long-term response to GDNF delivery that also occurs in Parkinson's disease patients.},
  author       = {Lindgren, Niklas and Francardo, Veronica and Quintino, Luis and Lundberg, Cecilia and Cenci Nilsson, Angela},
  issn         = {1877-718X},
  keyword      = {Neurotoxin,neuroprotection,rodent,mitogen-activated protein kinases,MAPK,trophic factor,GDNF},
  language     = {eng},
  number       = {4},
  pages        = {333--348},
  publisher    = {IOS Press},
  series       = {Journal of Parkinson's Disease},
  title        = {A Model of GDNF Gene Therapy in Mice with 6-Hydroxydopamine Lesions: Time Course of Neurorestorative Effects and ERK1/2 Activation},
  url          = {http://dx.doi.org/10.3233/JPD-012146},
  volume       = {2},
  year         = {2012},
}