Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual and developmental disabilities. The disease is caused by the loss of function of maternally inherited UBE3A, a gene that exhibits paternal-specific imprinting in neuronal tissues. Ube3a-maternal deficient mi...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-09-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996117301225 |
| _version_ | 1818576267045240832 |
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| author | Imran Jamal Vipendra Kumar Naman Vatsa Shashi Shekhar Brijesh Kumar Singh Ankit Sharma Nihar Ranjan Jana |
| author_facet | Imran Jamal Vipendra Kumar Naman Vatsa Shashi Shekhar Brijesh Kumar Singh Ankit Sharma Nihar Ranjan Jana |
| author_sort | Imran Jamal |
| collection | DOAJ |
| description | Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual and developmental disabilities. The disease is caused by the loss of function of maternally inherited UBE3A, a gene that exhibits paternal-specific imprinting in neuronal tissues. Ube3a-maternal deficient mice (AS mice) display many classical features of AS, although, the underlying mechanism of these behavioural deficits is poorly understood. Here we report that the absence of Ube3a in AS mice brain caused aberrant increase in HDAC1/2 along with decreased acetylation of histone H3/H4. Partial knockdown of Ube3a in cultured neuronal cells also lead to significant up-regulation of HDAC1/2 and consequent down-regulation of histones H3/H4 acetylation. Treatment of HDAC inhibitor, sodium valproate, to AS mice showed significant improvement in social, cognitive and motor impairment along with restoration of various proteins linked with synaptic function and plasticity. Interestingly, HDAC inhibitor also significantly increased the expression of Ube3a in cultured neuronal cells and in the brain of wild type mice but not in AS mice. These results indicate that anomalous HDAC1/2 activity might be linked with synaptic dysfunction and behavioural deficits in AS mice and suggests that HDAC inhibitors could be potential therapeutic molecule for the treatment of the disease. |
| first_indexed | 2024-12-16T06:11:18Z |
| format | Article |
| id | doaj.art-9123999952ca4bceb2a5d48f68635630 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T06:11:18Z |
| publishDate | 2017-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-9123999952ca4bceb2a5d48f686356302022-12-21T22:41:23ZengElsevierNeurobiology of Disease1095-953X2017-09-0110599108Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndromeImran Jamal0Vipendra Kumar1Naman Vatsa2Shashi Shekhar3Brijesh Kumar Singh4Ankit Sharma5Nihar Ranjan Jana6Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon - 122 051, IndiaCellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon - 122 051, IndiaCellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon - 122 051, IndiaCellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon - 122 051, IndiaCellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon - 122 051, IndiaCellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon - 122 051, IndiaCorresponding author.; Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon - 122 051, IndiaAngelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual and developmental disabilities. The disease is caused by the loss of function of maternally inherited UBE3A, a gene that exhibits paternal-specific imprinting in neuronal tissues. Ube3a-maternal deficient mice (AS mice) display many classical features of AS, although, the underlying mechanism of these behavioural deficits is poorly understood. Here we report that the absence of Ube3a in AS mice brain caused aberrant increase in HDAC1/2 along with decreased acetylation of histone H3/H4. Partial knockdown of Ube3a in cultured neuronal cells also lead to significant up-regulation of HDAC1/2 and consequent down-regulation of histones H3/H4 acetylation. Treatment of HDAC inhibitor, sodium valproate, to AS mice showed significant improvement in social, cognitive and motor impairment along with restoration of various proteins linked with synaptic function and plasticity. Interestingly, HDAC inhibitor also significantly increased the expression of Ube3a in cultured neuronal cells and in the brain of wild type mice but not in AS mice. These results indicate that anomalous HDAC1/2 activity might be linked with synaptic dysfunction and behavioural deficits in AS mice and suggests that HDAC inhibitors could be potential therapeutic molecule for the treatment of the disease.http://www.sciencedirect.com/science/article/pii/S0969996117301225Angelman syndromeUbe3aHDACSodium valproate, HDAC inhibitor |
| spellingShingle | Imran Jamal Vipendra Kumar Naman Vatsa Shashi Shekhar Brijesh Kumar Singh Ankit Sharma Nihar Ranjan Jana Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome Neurobiology of Disease Angelman syndrome Ube3a HDAC Sodium valproate, HDAC inhibitor |
| title | Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome |
| title_full | Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome |
| title_fullStr | Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome |
| title_full_unstemmed | Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome |
| title_short | Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome |
| title_sort | rescue of altered hdac activity recovers behavioural abnormalities in a mouse model of angelman syndrome |
| topic | Angelman syndrome Ube3a HDAC Sodium valproate, HDAC inhibitor |
| url | http://www.sciencedirect.com/science/article/pii/S0969996117301225 |
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