Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway
Machado–Joseph disease (MJD) is a neurodegenerative disorder characterized by an abnormal expansion of the CAG triplet in the ATXN3 gene, translating into a polyglutamine tract within the ataxin-3 protein. The available treatments only ameliorate symptomatology and do not block disease progression....
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/1721.1/106599 https://orcid.org/0000-0003-4064-2510 |
| _version_ | 1826208063730745344 |
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| author | Cunha-Santos, Janete Duarte-Neves, Joana Carmona, Vitor Pereira de Almeida, Luís Cavadas, Cláudia Guarente, Leonard Pershing |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Cunha-Santos, Janete Duarte-Neves, Joana Carmona, Vitor Pereira de Almeida, Luís Cavadas, Cláudia Guarente, Leonard Pershing |
| author_sort | Cunha-Santos, Janete |
| collection | MIT |
| description | Machado–Joseph disease (MJD) is a neurodegenerative disorder characterized by an abnormal expansion of the CAG triplet in the ATXN3 gene, translating into a polyglutamine tract within the ataxin-3 protein. The available treatments only ameliorate symptomatology and do not block disease progression. In this study we find that caloric restriction dramatically
rescues the motor incoordination, imbalance and the associated neuropathology in transgenic MJD mice. We further show that caloric restriction rescues SIRT1 levels in transgenic MJD mice, whereas silencing SIRT1 is sufficient to prevent the beneficial effects on MJD pathology.
In addition, the re-establishment of SIRT1 levels in MJD mouse model, through the gene delivery approach, significantly ameliorates neuropathology, reducing neuroinflammation and activating autophagy. Furthermore, the pharmacological activation of SIRT1 with resveratrol
significantly reduces motor incoordination of MJD mice. The pharmacological SIRT1 activation could provide important benefits to treat MJD patients. |
| first_indexed | 2024-09-23T13:59:56Z |
| format | Article |
| id | mit-1721.1/106599 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:59:56Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1065992022-10-01T18:28:09Z Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway Cunha-Santos, Janete Duarte-Neves, Joana Carmona, Vitor Pereira de Almeida, Luís Cavadas, Cláudia Guarente, Leonard Pershing Massachusetts Institute of Technology. Department of Biology Paul F. Glenn Center for Biology of Aging Research (Massachusetts Institute of Technology) Koch Institute for Integrative Cancer Research at MIT Guarente, Leonard Pershing Machado–Joseph disease (MJD) is a neurodegenerative disorder characterized by an abnormal expansion of the CAG triplet in the ATXN3 gene, translating into a polyglutamine tract within the ataxin-3 protein. The available treatments only ameliorate symptomatology and do not block disease progression. In this study we find that caloric restriction dramatically rescues the motor incoordination, imbalance and the associated neuropathology in transgenic MJD mice. We further show that caloric restriction rescues SIRT1 levels in transgenic MJD mice, whereas silencing SIRT1 is sufficient to prevent the beneficial effects on MJD pathology. In addition, the re-establishment of SIRT1 levels in MJD mouse model, through the gene delivery approach, significantly ameliorates neuropathology, reducing neuroinflammation and activating autophagy. Furthermore, the pharmacological activation of SIRT1 with resveratrol significantly reduces motor incoordination of MJD mice. The pharmacological SIRT1 activation could provide important benefits to treat MJD patients. Fonds Europeen de Developpement Economique et Regional (Grant CENTRO-07-ST24-FEDER-002002) French Muscular Dystrophy Association (AFM-Téléthon) National Ataxia Foundation Richard Chin and Lily Lock Machado-Joseph Disease Research Fund Fundação para a Ciência e a Tecnologia (Portugal) (Strategic Project UID/NEU/04539/2013, E-Rare4/0003/2012) 2017-01-24T17:16:28Z 2017-01-24T17:16:28Z 2016-05 2015-08 Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/106599 Cunha-Santos, Janete et al. “Caloric Restriction Blocks Neuropathology and Motor Deficits in Machado–Joseph Disease Mouse Models through SIRT1 Pathway.” Nature Communications 7 (2016): 11445. https://orcid.org/0000-0003-4064-2510 en_US http://dx.doi.org/10.1038/ncomms11445 Nature Communications Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature |
| spellingShingle | Cunha-Santos, Janete Duarte-Neves, Joana Carmona, Vitor Pereira de Almeida, Luís Cavadas, Cláudia Guarente, Leonard Pershing Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway |
| title | Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway |
| title_full | Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway |
| title_fullStr | Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway |
| title_full_unstemmed | Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway |
| title_short | Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway |
| title_sort | caloric restriction blocks neuropathology and motor deficits in machado joseph disease mouse models through sirt1 pathway |
| url | http://hdl.handle.net/1721.1/106599 https://orcid.org/0000-0003-4064-2510 |
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