Genetically engineered mouse models of the trinucleotide-repeat spinocerebellar ataxias

Melissa A C Ingram, Harry T Orr, H. Brent Clark

Research output: Contribution to journalReview article

11 Citations (Scopus)

Abstract

The spinocerebellar ataxias (SCAs) are dominantly inherited disorders that primarily affect coordination of motor function but also frequently involve other brain functions. The models described in this review address mechanisms of trinucleotide-repeat expansions, particularly those relating to polyglutamine expression in the mutant proteins. Modeling chronic late-onset human ataxias in mice is difficult because of their short life-span. While this potential hindrance has been partially overcome by using over-expression of the mutant gene, and/or worsening of the mutation by increasing the length of the trinucleotide repeat expansion, interpretation of results from such models and extrapolation to the human condition should be cautious. Nevertheless, genetically engineered murine models of these diseases have enhanced our understanding of the pathogenesis of many of these conditions. A common theme in many of the polyglutamine-repeat diseases is nuclear localization of mutant protein, with resultant effects on gene regulation. Conditional mutant models and transgenic knock-down therapy have demonstrated the potential for reversibility of disease when production of mutant protein is halted. Several other genetically engineered murine models of SCA also have begun to show utility in the identification and assessment of more classical drug-based therapeutic modalities.

Original languageEnglish (US)
Pages (from-to)33-42
Number of pages10
JournalBrain Research Bulletin
Volume88
Issue number1
DOIs
StatePublished - May 1 2012

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Spinocerebellar Ataxias
Trinucleotide Repeats
Mutant Proteins
Trinucleotide Repeat Expansion
Ataxia
Gene Expression
Mutation
Brain
Therapeutics
Pharmaceutical Preparations
Genes
polyglutamine

Keywords

  • Purkinje cell
  • Spinocerebellar ataxia
  • Transgenic mice
  • Trinucleotide repeat disease

Cite this

Genetically engineered mouse models of the trinucleotide-repeat spinocerebellar ataxias. / Ingram, Melissa A C; Orr, Harry T; Clark, H. Brent.

In: Brain Research Bulletin, Vol. 88, No. 1, 01.05.2012, p. 33-42.

Research output: Contribution to journalReview article

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