RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2
Episodic ataxia type-2 (EA2) is a dominantly inherited human neurological disorder caused by loss of function mutations in the CACNA1A gene, which encodes the CaV2.1 subunit of P/Q-type voltage-gated calcium channels. It remains however unknown whether the deficit of cerebellar CaV2.1 in adult is in...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-08-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114000941 |
| _version_ | 1818675890072059904 |
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| author | Julie Salvi Federica Bertaso Anne-Laure Mausset-Bonnefont Alexandra Metz Céline Lemmers Fabrice Ango Laurent Fagni Philippe Lory Alexandre Mezghrani |
| author_facet | Julie Salvi Federica Bertaso Anne-Laure Mausset-Bonnefont Alexandra Metz Céline Lemmers Fabrice Ango Laurent Fagni Philippe Lory Alexandre Mezghrani |
| author_sort | Julie Salvi |
| collection | DOAJ |
| description | Episodic ataxia type-2 (EA2) is a dominantly inherited human neurological disorder caused by loss of function mutations in the CACNA1A gene, which encodes the CaV2.1 subunit of P/Q-type voltage-gated calcium channels. It remains however unknown whether the deficit of cerebellar CaV2.1 in adult is in direct link with the disease. To address this issue, we have used lentiviral based-vector RNA interference (RNAi) to knock-down CaV2.1 expression in the cerebellum of adult mice. We show that suppression of the P/Q-type channels in Purkinje neurons induced motor abnormalities, such as imbalance and ataxic gait. Interestingly, moderate channel suppression caused no basal ataxia, while β-adrenergic activation and exercise mimicked stress induced motor disorders. Moreover, stress-induced ataxia was stable, non-progressive and totally abolished by acetazolamide, a carbonic anhydrase inhibitor used to treat EA2. Altogether, these data reveal that P/Q-type channel suppression in adult mice supports the episodic status of EA2 disease. |
| first_indexed | 2024-12-17T08:34:46Z |
| format | Article |
| id | doaj.art-134a4839fbb746e09ea46831f9f608f2 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T08:34:46Z |
| publishDate | 2014-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-134a4839fbb746e09ea46831f9f608f22022-12-21T21:56:30ZengElsevierNeurobiology of Disease1095-953X2014-08-01684756RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2Julie Salvi0Federica Bertaso1Anne-Laure Mausset-Bonnefont2Alexandra Metz3Céline Lemmers4Fabrice Ango5Laurent Fagni6Philippe Lory7Alexandre Mezghrani8Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Labex ICST Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, FranceInstitut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, FranceInstitut des Neurosciences de Montpellier, INSERM U844, Hôpital Saint Eloi, Bâtiment 80, rue Augustin Fliche, BP74103, 34091 Montpellier cedex 05, FranceInstitut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Labex ICST Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, FranceInstitut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Labex ICST Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Plateforme de Vectorologie de Montpellier (PVM), Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, FranceInstitut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, FranceInstitut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, FranceInstitut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Labex ICST Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Corresponding authors at: Institut de Génomique Fonctionnelle, UMR 5203 CNRS, U661 INSERM, Univ. Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France.Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Labex ICST Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Corresponding authors at: Institut de Génomique Fonctionnelle, UMR 5203 CNRS, U661 INSERM, Univ. Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France.Episodic ataxia type-2 (EA2) is a dominantly inherited human neurological disorder caused by loss of function mutations in the CACNA1A gene, which encodes the CaV2.1 subunit of P/Q-type voltage-gated calcium channels. It remains however unknown whether the deficit of cerebellar CaV2.1 in adult is in direct link with the disease. To address this issue, we have used lentiviral based-vector RNA interference (RNAi) to knock-down CaV2.1 expression in the cerebellum of adult mice. We show that suppression of the P/Q-type channels in Purkinje neurons induced motor abnormalities, such as imbalance and ataxic gait. Interestingly, moderate channel suppression caused no basal ataxia, while β-adrenergic activation and exercise mimicked stress induced motor disorders. Moreover, stress-induced ataxia was stable, non-progressive and totally abolished by acetazolamide, a carbonic anhydrase inhibitor used to treat EA2. Altogether, these data reveal that P/Q-type channel suppression in adult mice supports the episodic status of EA2 disease.http://www.sciencedirect.com/science/article/pii/S0969996114000941P/Q-type calcium channelMouseCerebellumPurkinje neuronRNA interferenceAtaxia |
| spellingShingle | Julie Salvi Federica Bertaso Anne-Laure Mausset-Bonnefont Alexandra Metz Céline Lemmers Fabrice Ango Laurent Fagni Philippe Lory Alexandre Mezghrani RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2 Neurobiology of Disease P/Q-type calcium channel Mouse Cerebellum Purkinje neuron RNA interference Ataxia |
| title | RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2 |
| title_full | RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2 |
| title_fullStr | RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2 |
| title_full_unstemmed | RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2 |
| title_short | RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2 |
| title_sort | rnai silencing of p q type calcium channels in purkinje neurons of adult mouse leads to episodic ataxia type 2 |
| topic | P/Q-type calcium channel Mouse Cerebellum Purkinje neuron RNA interference Ataxia |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114000941 |
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