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:
https://lup.lub.lu.se/record/1883273
- author
- Horvath, Lazlo
; van Marion, Ingrid
LU
; Tai, Khalid
LU
; Tolstrup Nielsen, Troels
and Lundberg, Cecilia
LU
- organization
- publishing date
- 2011
- 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 Inc.
- 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
- 2016-04-01 10:19:22
- date last changed
- 2022-01-25 22:07:23
@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}},
keywords = {{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 Inc.}},
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}},
doi = {{10.1002/jgm.1555}},
volume = {{13}},
year = {{2011}},
}