title: Caloric restriction blocks neuropathology and motor deficits in Machado-Joseph disease mouse models through SIRT1 pathway.
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.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal.|Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Janete
authors.initials: J
authors.lastname: Cunha-Santos
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal.|Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Duarte-Neves
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal.|Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Vitor
authors.initials: V
authors.lastname: Carmona
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Glenn Laboratory for the Science of Aging, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal.|Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Pereira de Almeida
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal.|Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Cavadas
mesh_terms: D000818:Animals; D000067699:Ataxin-3 / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D031204:Caloric Restriction; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005684:Gait; D007249:Inflammation / Q000473:pathology; D017827:Machado-Joseph Disease / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D050505:Mutant Proteins / Q000378:metabolism; D009420:Nervous System / Q000187:drug effects / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D050505:Mutant Proteins; D012333:RNA, Messenger; D013267:Stilbenes; D000067699:Ataxin-3; D056564:Sirtuin 1; D000077185:Resveratrol