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Knock down of GAD67 protein levels normalizes neuronal activity in a rat model of Parkinson's disease.

Horvath, Lazlo; van Marion, Ingrid LU ; Tai, Khalid LU ; Tolstrup Nielsen, Troels and Lundberg, Cecilia LU (2011) In Journal of Gene Medicine 13(3). p.188-197
Abstract
BACKGROUND: Dopamine depletion of the striatum is one of the hallmarks of Parkinson's disease. The loss of dopamine upregulates GAD67 expression in the striatal projection neurons and causes other changes in the activity of the basal ganglia circuit. METHODS: To normalize the GAD67 expression in the striatum after dopamine depletion we developed several lentiviral vectors that express RNAi directed against GAD67 mRNA. The vectors were injected into the striatum of hemiparkinsonian rats and the level of GAD67 protein as well as a marker of neuronal activity, mtCO1, was analyzed using Western blots. RESULTS: Unilateral lesions of the dopamine neurons in substantia nigra resulted in an increased level of GAD67 protein in the ipsilateral... (More)
BACKGROUND: Dopamine depletion of the striatum is one of the hallmarks of Parkinson's disease. The loss of dopamine upregulates GAD67 expression in the striatal projection neurons and causes other changes in the activity of the basal ganglia circuit. METHODS: To normalize the GAD67 expression in the striatum after dopamine depletion we developed several lentiviral vectors that express RNAi directed against GAD67 mRNA. The vectors were injected into the striatum of hemiparkinsonian rats and the level of GAD67 protein as well as a marker of neuronal activity, mtCO1, was analyzed using Western blots. RESULTS: Unilateral lesions of the dopamine neurons in substantia nigra resulted in an increased level of GAD67 protein in the ipsilateral striatum. Furthermore, we detected significantly higher levels of mtCO1, after dopamine depletion in the striatum. Using a lentiviral vectors with a synthetic miRNA scaffold to deliver RNAi we were able to normalize the GAD67 protein levels in the parkinsonian rat striatum. In addition, we were able to normalize the increased neural activity, which resulted from the loss of dopamine as measured by the marker mtCO1. CONCLUSIONS: We conclude that RNAi directed against GAD67 may be a valid approach to correct the dysregulation of the basal ganglia circuit in a rat model of Parkinson's disease. The possibility to correct for a loss of dopamine using non-dopamimetic tools is interesting as it may be more directed towards the casual mechanisms of the motor symptoms. Copyright © 2011 John Wiley & Sons, Ltd. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
6-hydroxydopamine lesion, GAD67, lentiviral vector, mtCO1, Parkinson's, disease, RNAi, striatum, synthetic miRNA
in
Journal of Gene Medicine
volume
13
issue
3
pages
188 - 197
publisher
John Wiley & Sons
external identifiers
  • wos:000291112100005
  • pmid:21449035
  • scopus:79955129749
ISSN
1521-2254
DOI
10.1002/jgm.1555
language
English
LU publication?
yes
id
456df0ba-5e28-4bf3-80bb-d1e8fe99cc4c (old id 1883273)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21449035?dopt=Abstract
date added to LUP
2011-04-01 22:45:05
date last changed
2017-10-22 03:12:23
@article{456df0ba-5e28-4bf3-80bb-d1e8fe99cc4c,
  abstract     = {BACKGROUND: Dopamine depletion of the striatum is one of the hallmarks of Parkinson's disease. The loss of dopamine upregulates GAD67 expression in the striatal projection neurons and causes other changes in the activity of the basal ganglia circuit. METHODS: To normalize the GAD67 expression in the striatum after dopamine depletion we developed several lentiviral vectors that express RNAi directed against GAD67 mRNA. The vectors were injected into the striatum of hemiparkinsonian rats and the level of GAD67 protein as well as a marker of neuronal activity, mtCO1, was analyzed using Western blots. RESULTS: Unilateral lesions of the dopamine neurons in substantia nigra resulted in an increased level of GAD67 protein in the ipsilateral striatum. Furthermore, we detected significantly higher levels of mtCO1, after dopamine depletion in the striatum. Using a lentiviral vectors with a synthetic miRNA scaffold to deliver RNAi we were able to normalize the GAD67 protein levels in the parkinsonian rat striatum. In addition, we were able to normalize the increased neural activity, which resulted from the loss of dopamine as measured by the marker mtCO1. CONCLUSIONS: We conclude that RNAi directed against GAD67 may be a valid approach to correct the dysregulation of the basal ganglia circuit in a rat model of Parkinson's disease. The possibility to correct for a loss of dopamine using non-dopamimetic tools is interesting as it may be more directed towards the casual mechanisms of the motor symptoms. Copyright © 2011 John Wiley & Sons, Ltd.},
  author       = {Horvath, Lazlo and van Marion, Ingrid and Tai, Khalid and Tolstrup Nielsen, Troels and Lundberg, Cecilia},
  issn         = {1521-2254},
  keyword      = {6-hydroxydopamine lesion,GAD67,lentiviral vector,mtCO1,Parkinson's,disease,RNAi,striatum,synthetic miRNA},
  language     = {eng},
  number       = {3},
  pages        = {188--197},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Gene Medicine},
  title        = {Knock down of GAD67 protein levels normalizes neuronal activity in a rat model of Parkinson's disease.},
  url          = {http://dx.doi.org/10.1002/jgm.1555},
  volume       = {13},
  year         = {2011},
}