title: RNA interference mitigates motor and neuropathological deficits in a cerebellar mouse model of Machado-Joseph disease.
abstract: Machado-Joseph disease or Spinocerebellar ataxia type 3 is a progressive fatal neurodegenerative disorder caused by the polyglutamine-expanded protein ataxin-3. Recent studies demonstrate that RNA interference is a promising approach for the treatment of Machado-Joseph disease. However, whether gene silencing at an early time-point is able to prevent the appearance of motor behavior deficits typical of the disease when initiated before onset of the disease had not been explored. Here, using a lentiviral-mediated allele-specific silencing of mutant ataxin-3 in an early pre-symptomatic cerebellar mouse model of Machado-Joseph disease we show that this strategy hampers the development of the motor and neuropathological phenotypic characteristics of the disease. At the histological level, the RNA-specific silencing of mutant ataxin-3 decreased formation of mutant ataxin-3 aggregates, preserved Purkinje cell morphology and expression of neuronal markers while reducing cell death. Importantly, gene silencing prevented the development of impairments in balance, motor coordination, gait and hyperactivity observed in control mice. These data support the therapeutic potential of RNA interference for Machado-Joseph disease and constitute a proof of principle of the beneficial effects of early allele-specific silencing for therapy of this disease.
authors.affiliation: CNC - Center for Neuroscience & Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Clévio
authors.initials: C
authors.lastname: Nóbrega
authors.affiliation: CNC - Center for Neuroscience & Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Nascimento-Ferreira
authors.affiliation: CNC - Center for Neuroscience & Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Onofre
authors.affiliation: Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal.
authors.forename: David
authors.initials: D
authors.lastname: Albuquerque
authors.affiliation: Lausanne University Hospital, Department of Clinical Neurosciences, Laboratory of Cellular and Molecular Neurotherapies, Lausanne, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.affiliation: CNC - Center for Neuroscience & Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
authors.forename: Luís Pereira
authors.initials: LP
authors.lastname: de Almeida
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D020868:Gene Silencing; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse