title: Neuropeptide Y mitigates neuropathology and motor deficits in mouse models of Machado-Joseph disease.
abstract: Machado-Joseph disease (MJD) is a fatal, dominantly inherited neurodegenerative disorder associated with an expanded polyglutamine tract within the ataxin-3 protein, and characterized by progressive impairment of motor coordination, associated with neurodegeneration of specific brain regions, including cerebellum and striatum. The currently available therapies do not allow modification of disease progression. Neuropeptide Y (NPY) has been shown to exert potent neuroprotective effects by multiple pathways associated with the MJD mechanisms of disease. Thus, we evaluated NPY levels in MJD and investigated whether raising NPY by gene transfer would alleviate neuropathological and behavioural deficits in cerebellar and striatal mouse models of the disease. For that, a cerebellar transgenic and a striatal lentiviral-based models of MJD were used. NPY overexpression in the affected brain regions in these two mouse models was obtained by stereotaxic injection of adeno-associated viral vectors encoding NPY. Up to 8 weeks after viral injection, balance and motor coordination behaviour and neuropathology were analysed. We observed that NPY levels were decreased in two MJD patients' cerebella and in striata and cerebella of disease mouse models. Furthermore, overexpression of NPY alleviated the motor coordination impairments and attenuated the related neuropathological parameters, preserving cerebellar volume and granular layer thickness, reducing striatal lesion and decreasing mutant ataxin-3 aggregation. Additionally, NPY mediated increase of brain-derived neurotrophic factor levels and decreased neuroinflammation markers. Our data suggest that NPY is a potential therapeutic strategy for MJD.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, 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, Coimbra 3004-517, Portugal.
authors.forename: Nélio
authors.initials: N
authors.lastname: Gonçalves
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, 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, Coimbra 3004-517, Portugal.
authors.forename: Ana Teresa
authors.initials: AT
authors.lastname: Simões
authors.affiliation: Department of Pathology, University of Groningen, Groningen 9712 CP, The Netherlands.
authors.forename: Wilfred F A
authors.initials: WF
authors.lastname: den Dunnen
authors.affiliation: Department of Neurophysiology, Gunma University Graduate School of Medicine, Gunma 971-8511, Japan and.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirai
authors.affiliation: Department of Neurology, Vector Laboratory, University of Göttingen, Göttingen 37073, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal, Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Cavadas
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal, Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal, luispa@cnc.uc.pt.
authors.forename: Luís
authors.initials: L
authors.lastname: Pereira de Almeida
mesh_terms: D000818:Animals; D000067699:Ataxin-3 / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism / Q000503:physiopathology*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009478:Neuropeptide Y / Q000235:genetics* / Q000378:metabolism*; D014793:Visual Cortex / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009478:Neuropeptide Y; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse