RNA interference mitigates motor and neuropathological deficits in a cerebellar mouse model of Machado-Joseph disease

• Published in: PloS one Vol. 9; no. 8; p. e100086
• Main Authors: Nóbrega, Clévio, Nascimento-Ferreira, Isabel, Onofre, Isabel, Albuquerque, David, Déglon, Nicole, de Almeida, Luís Pereira
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21-08-2014; Public Library of Science (PLoS)
• Subjects: Alleles; Alzheimer's disease; Analysis; Animals; Ataxia; Ataxin; Ataxin-3; Balance; Biology; Biology and life sciences; Cell death; Cell morphology; Cerebellar ataxia; Cerebellum; Cerebellum - metabolism; Cerebellum - pathology; Coordination; Cytology; Disease Models, Animal; Gait; Gene expression; Gene Silencing; Gene therapy; Genetic engineering; Genotype & phenotype; Hyperactivity; Interference; Machado-Joseph disease; Machado-Joseph Disease - genetics; Machado-Joseph Disease - metabolism; Machado-Joseph Disease - pathology; Medical treatment; Medicine and Health Sciences; Mice; Motor ability; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neuropathology; Neurosciences; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pharmacy; Polyglutamine; Proteins; Research and Analysis Methods; Ribonucleic acid; RNA; RNA interference; RNA Interference - physiology; RNA-mediated interference; Rodents; Transcription Factors - genetics; Transcription Factors - metabolism; Trinucleotide repeat diseases; Vectors (Biology); Portugal
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0100086

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.