Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7

Pavitra S Ramachandran; Ryan L Boudreau; Kellie A Schaefer; Albert R La Spada; Beverly L Davidson

doi:10.1038/mt.2014.108

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Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7

Journal article

Open access

Peer reviewed

Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7

Pavitra S Ramachandran, Ryan L Boudreau, Kellie A Schaefer, Albert R La Spada and Beverly L Davidson

Molecular therapy, Vol.22(9), pp.1635-1642

09/2014

DOI: 10.1038/mt.2014.108

PMCID: PMC4435484

PMID: 24930601

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Abstract

Spinocerebellar ataxia type 7 (SCA7) is a late-onset neurodegenerative disease characterized by ataxia and vision loss with no effective treatments in the clinic. The most striking feature is the degeneration of Purkinje neurons of the cerebellum caused by the presence of polyglutamine-expanded ataxin-7. Ataxin-7 is part of a transcriptional complex, and, in the setting of mutant ataxin-7, there is misregulation of target genes. Here, we designed RNAi sequences to reduce the expression of both wildtype and mutant ataxin-7 to test if reducing ataxin-7 in Purkinje cells is both tolerated and beneficial in an animal model of SCA7. We observed sustained reduction of both wildtype and mutant ataxin-7 as well as a significant improvement of ataxia phenotypes. Furthermore, we observed a reduction in cerebellar molecular layer thinning and nuclear inclusions, a hallmark of SCA7. In addition, we observed recovery of cerebellar transcripts whose expression is disrupted in the presence of mutant ataxin-7. These data demonstrate that reduction of both wildtype and mutant ataxin-7 by RNAi is well tolerated, and contrary to what may be expected from reducing a component of the Spt-Taf9-Gcn5 acetyltransferase complex, is efficacious in the SCA7 mouse.

Nerve Tissue Proteins - antagonists & inhibitors

Purkinje Cells - metabolism

Mice, Inbred C57BL

Gene Expression Regulation

Ataxin-7

Spinocerebellar Ataxias - physiopathology

Spinocerebellar Ataxias - therapy

Motor Activity

Nerve Tissue Proteins - genetics

Animals

RNA Interference

Alleles

Mice

Mutation

Purkinje Cells - pathology

Disease Models, Animal

Spinocerebellar Ataxias - genetics

Details

Title: Subtitle: Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7
Creators: Pavitra S Ramachandran - Interdisciplinary program in Genetics, University of Iowa, Iowa City, Iowa, USA
Ryan L Boudreau - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Kellie A Schaefer - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Albert R La Spada - Department of Pediatrics, Cellular and Molecular Medicine, and Neurosciences, Division of Biological Sciences, the Institute for Genomic Medicine, and the Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California, USA
Beverly L Davidson - 1] Interdisciplinary program in Genetics, University of Iowa, Iowa City, Iowa, USA Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA Department of Neurology, University of Iowa, Iowa City, Iowa, USA Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA
Resource Type: Journal article
Publication Details: Molecular therapy, Vol.22(9), pp.1635-1642
DOI: 10.1038/mt.2014.108
PMID: 24930601
PMCID: PMC4435484
NLM abbreviation: Mol Ther
ISSN: 1525-0016
eISSN: 1525-0024
Publisher: United States
Grant note: R01 HD44093 / NICHD NIH HHS P01 NS50210 / NINDS NIH HHS R01 HD044093 / NICHD NIH HHS P01 NS050210 / NINDS NIH HHS R21 NS082112 / NINDS NIH HHS R01 EY014061 / NEI NIH HHS
Language: English
Date published: 09/2014
Academic Unit: Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984065482302771

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