Journal article
Silencing Mutant ATXN3 Expression Resolves Molecular Phenotypes in SCA3 Transgenic Mice
Molecular therapy, Vol.21(10), pp.1909-1918
10/2013
DOI: 10.1038/mt.2013.152
PMCID: PMC3808130
PMID: 23820820
Abstract
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a polyglutamine expansion in the deubiquitinating enzyme, Ataxin-3. Currently, there are no effective treatments for this fatal disorder but studies support the hypothesis that reducing mutant Ataxin-3 protein levels might reverse or halt the progression of disease in SCA3. Here, we sought to modulate
ATXN3
expression
in vivo
using RNA interference. We developed artificial microRNA mimics targeting the 3′-untranslated region (3′UTR) of human
ATXN3
and then used recombinant adeno-associated virus to deliver them to the cerebellum of transgenic mice expressing the full human disease gene (SCA3/MJD84.2 mice). Anti-
ATXN3
microRNA mimics effectively suppressed human
ATXN3
expression in SCA3/MJD84.2 mice. Short-term treatment cleared the abnormal nuclear accumulation of mutant Ataxin-3 throughout the transduced SCA3/MJD84.2 cerebellum. Analysis also revealed changes in the steady-state levels of specific microRNAs in the cerebellum of SCA3/MJD84.2 mice, a previously uncharacterized molecular phenotype of SCA3 that appears to be dependent on mutant Ataxin-3 expression. Our findings support the preclinical development of molecular therapies aimed at halting the expression of
ATXN3
as a viable approach to SCA3 and point to microRNA deregulation as a potential surrogate marker of SCA3 pathogenesis.
Details
- Title: Subtitle
- Silencing Mutant ATXN3 Expression Resolves Molecular Phenotypes in SCA3 Transgenic Mice
- Creators
- Edgardo Rodríguez-Lebrón - , Iowa City, IowaMaria doCarmo Costa - , Ann Arbor, MichiganKatiuska Luna-Cancalon - , Ann Arbor, MichiganTherese M Peron - , Ann Arbor, MichiganSvetlana Fischer - , Ann Arbor, MichiganRyan L Boudreau - , Iowa City, IowaBeverly L Davidson - , Iowa City, IowaHenry L Paulson - , Ann Arbor, Michigan
- Resource Type
- Journal article
- Publication Details
- Molecular therapy, Vol.21(10), pp.1909-1918
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/mt.2013.152
- PMID
- 23820820
- PMCID
- PMC3808130
- ISSN
- 1525-0016
- eISSN
- 1525-0024
- Language
- English
- Date published
- 10/2013
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984070215302771
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