1. Caloric restriction blocks neuropathology and motor deficits in Machado–Joseph disease mouse models through SIRT1 pathway
- Author
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Vitor Carmona, Janete Cunha-Santos, Luís Pereira de Almeida, Cláudia Cavadas, Joana Duarte-Neves, Leonard Guarente, 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, and Guarente, Leonard Pershing
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Science ,Transgene ,General Physics and Astronomy ,Mice, Transgenic ,Neuropathology ,Biology ,Motor Activity ,Bioinformatics ,Nervous System ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Sirtuin 1 ,Cell Line, Tumor ,Cerebellum ,Stilbenes ,medicine ,Autophagy ,Gene silencing ,Animals ,RNA, Messenger ,Ataxin-3 ,Gait ,Neuroinflammation ,Caloric Restriction ,Genetics ,Inflammation ,Neurons ,Multidisciplinary ,General Chemistry ,Machado-Joseph Disease ,Polyglutamine tract ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Resveratrol ,biology.protein ,Mutant Proteins ,Machado–Joseph disease ,030217 neurology & neurosurgery - Abstract
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. Competitive Factors Operational Program (CENTRO-07-ST24-FEDER-002002), Fundação para a Ciência e a Tecnologia (Portugal) (Strategic Project UID/NEU/04539/2013, E-Rare4/0003/2012), French Muscular Dystrophy Association (AFM-Téléthon), National Ataxia Foundation, Richard Chin and Lily Lock Machado-Joseph Disease Research Fund
- Published
- 2015