Search: onr:"swepub:oai:lup.lub.lu.se:5266c079-7303-4f41-a0d4-3b731105035e" >
A Model of GDNF Gen...
A Model of GDNF Gene Therapy in Mice with 6-Hydroxydopamine Lesions: Time Course of Neurorestorative Effects and ERK1/2 Activation
-
- Lindgren, Niklas (author)
- Lund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups
-
- Francardo, Veronica (author)
- Lund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups
-
- Quintino, Luis (author)
- Lund University,Lunds universitet,CNS Genterapi,Forskargrupper vid Lunds universitet,CNS Gene Therapy,Lund University Research Groups
-
show more...
-
- Lundberg, Cecilia (author)
- Lund University,Lunds universitet,CNS Genterapi,Forskargrupper vid Lunds universitet,CNS Gene Therapy,Lund University Research Groups
-
- Cenci Nilsson, Angela (author)
- Lund University,Lunds universitet,Basala gangliernas patofysiologi,Forskargrupper vid Lunds universitet,Basal Ganglia Pathophysiology,Lund University Research Groups
-
show less...
-
(creator_code:org_t)
- 2012
- 2012
- English.
-
In: Journal of Parkinson's Disease. - 1877-718X. ; 2:4, s. 333-348
- Related links:
-
https://portal.resea... (primary) (free)
-
show more...
-
http://dx.doi.org/10...
-
https://lup.lub.lu.s...
-
https://doi.org/10.3...
-
show less...
Abstract
Subject headings
Close
- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Keyword
- Neurotoxin
- neuroprotection
- rodent
- mitogen-activated protein kinases
- MAPK
- trophic factor
- GDNF
Publication and Content Type
- art (subject category)
- ref (subject category)
Find in a library
To the university's database