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.
Highlights
Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is a dominant fatal inherited disorder of the central nervous system (CNS) caused by overrepetition of the CAG trinucleotide in the coding region of the MJD1/ATXN3 gene, which encodes the ataxin-3 protein (Atx3) [1]
To explore the outcome of mutant ataxin-3 gene silencing in MJD motor phenotype and neuropathology, lentiviral vectors encoding RNA interference transcripts were co-injected with the human full-length mutant ataxin-3 in the cerebellum of wild-type mice (Figure S1 in File S1)
We investigated whether allele-specific gene silencing initiated before onset of symptoms would alleviate MJD
Summary
Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is a dominant fatal inherited disorder of the central nervous system (CNS) caused by overrepetition of the CAG trinucleotide in the coding region of the MJD1/ATXN3 gene, which encodes the ataxin-3 protein (Atx3) [1]. A common hallmark of the disease is the accumulation of abnormally misfolded protein, typically in the form of intranuclear neuronal inclusions [7] in affected brain regions, such as afferent and efferent cerebellar systems, substantia nigra, cranial nerve motor nuclei [5] and striatum [8,9,10,11]. MJD is the most common ataxia worldwide [12] and to most other polyglutamine diseases no treatment is available
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