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: Clévio Nóbrega, Isabel Nascimento-Ferreira, Isabel Onofre, David Albuquerque, Nicole Déglon, Luís Pereira de Almeida
• Journal: PloS one (PLoS One) Vol. 9 Issue 8 Pg. e100086 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25144231 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nuclear Proteins
• Transcription Factors
• Ataxin-3
• Atxn3 protein, mouse

Topics

• Animals
• Ataxin-3
• Cerebellum (metabolism, pathology)
• Disease Models, Animal
• Gene Silencing
• Machado-Joseph Disease (genetics, metabolism, pathology)
• Mice
• Nuclear Proteins (genetics, metabolism)
• RNA Interference (physiology)
• Transcription Factors (genetics, metabolism)