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Title: RNA Interference Mitigates Motor and Neuropathological Deficits in a Cerebellar Mouse Model of Machado-Joseph Disease
Authors: Nóbrega, Clévio 
Nascimento-Ferreira, Isabel 
Onofre, Isabel 
Albuquerque, David 
Déglon, Nicole 
Almeida, Luís Pereira de 
Issue Date: 21-Aug-2014
Publisher: PLOS
Citation: NÓBREGA, Clévio [et. al] - RNA Interference Mitigates Motor and Neuropathological Deficits in a Cerebellar Mouse Model of Machado-Joseph Disease. "PLOS one". ISSN 1932-6203. Vol. 9 Nº. 8 (2014) p. e100086
Serial title, monograph or event: PLOS one
Volume: 9
Issue: 8
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 allelespecific silencing for therapy of this disease.
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0100086
Rights: openAccess
Appears in Collections:FFUC- Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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