Knockdown of GAD67 protein levels normalizes neuronal activity in a rat model of Parkinson's disease
Identifieur interne : 000276 ( Main/Exploration ); précédent : 000275; suivant : 000277Knockdown of GAD67 protein levels normalizes neuronal activity in a rat model of Parkinson's disease
Auteurs : Lazlo Horvath [Suède] ; Ingrid Van Marion [Suède] ; Khalid Taï [Suède] ; Troels Tolstrup Nielsen [Danemark] ; Cecilia Lundberg [Suède]Source :
- The Journal of Gene Medicine [ 1099-498X ] ; 2011-03.
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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 RNA interference (RNAi) directed against GAD67 mitochondrial RNA. 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 nondopamimetic tools is interesting because it may be more directed towards the casual mechanisms of the motor symptoms. Copyright © 2011 John Wiley & Sons, Ltd.
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DOI: 10.1002/jgm.1555
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Gene Med.</title><idno type="ISSN">1099-498X</idno><idno type="eISSN">1521-2254</idno><imprint><publisher>John Wiley & Sons, Ltd.</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2011-03">2011-03</date><biblScope unit="volume">13</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="188">188</biblScope><biblScope unit="page" to="197">197</biblScope></imprint><idno type="ISSN">1099-498X</idno></series><idno type="istex">3DBCFF07CBE2F7B1C991F110E47C53447823F5D7</idno><idno type="DOI">10.1002/jgm.1555</idno><idno type="ArticleID">JGM1555</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1099-498X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>6‐hydroxydopamine lesion</term><term>GAD67</term><term>Parkinson's disease</term><term>RNAi</term><term>lentiviral vector</term><term>mtCO1</term><term>striatum</term><term>synthetic miRNA</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 RNA interference (RNAi) directed against GAD67 mitochondrial RNA. 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 nondopamimetic tools is interesting because it may be more directed towards the casual mechanisms of the motor symptoms. Copyright © 2011 John Wiley & Sons, Ltd.</div></front></TEI><affiliations><list><country><li>Danemark</li><li>Suède</li></country><region><li>Hovedstaden</li></region><settlement><li>Copenhague</li></settlement></list><tree><country name="Suède"><noRegion><name sortKey="Horvath, Lazlo" sort="Horvath, Lazlo" uniqKey="Horvath L" first="Lazlo" last="Horvath">Lazlo Horvath</name></noRegion><name sortKey="Lundberg, Cecilia" sort="Lundberg, Cecilia" uniqKey="Lundberg C" first="Cecilia" last="Lundberg">Cecilia Lundberg</name><name sortKey="Tai, Khalid" sort="Tai, Khalid" uniqKey="Tai K" first="Khalid" last="Taï">Khalid Taï</name><name sortKey="Van Marion, Ingrid" sort="Van Marion, Ingrid" uniqKey="Van Marion I" first="Ingrid" last="Van Marion">Ingrid Van Marion</name></country><country name="Danemark"><region name="Hovedstaden"><name sortKey="Nielsen, Troels Tolstrup" sort="Nielsen, Troels Tolstrup" uniqKey="Nielsen T" first="Troels Tolstrup" last="Nielsen">Troels Tolstrup Nielsen</name></region><name sortKey="Nielsen, Troels Tolstrup" sort="Nielsen, Troels Tolstrup" uniqKey="Nielsen T" first="Troels Tolstrup" last="Nielsen">Troels Tolstrup Nielsen</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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