Allele-Specific Conditional Destabilization of Glutamine Repeat mRNAs

Authors: CROUSE, ANDREW B.¹; DETLOFF, PETER J.²

Source: Gene Expression, Volume 12, Number 3, 2005 , pp. 213-222(10)

Publisher: Cognizant Communication Corporation

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Abstract:

Several late-onset neurological diseases are caused by the inheritance of an expanded CAG repeat coding for polyglutamine. To date there is no effective means of halting the progression of these diseases, and their underlying molecular mechanisms remain a mystery. Strategies designed to specifically reduce the levels of long repeat mRNA might provide an effective therapy for these diseases. An emphasis on allele specificity is necessary to avoid the potential toxicities associated with reduction of expression. The experiments described here are based on the relationship between translation and mRNA stability and the idea that translation of a repeated codon might be extremely sensitive to reductions in levels of cognate aminoacylated tRNA. Consistent with this hypothesis, we have discovered that reduced glutamine concentration destabilizes mRNAs coding for long glutamine repeats while sparing short repeat versions of the same mRNAs. These results suggest therapy might be attained with existing compounds or environmental conditions known to decrease free glutamine levels.

Keywords: Polyglutamine; Huntington's disease; Glutamine; tRNA; Translation; mRNA stability; Rational therapeutic

Document Type: Review article

Affiliations: 1: Department of Biochemistry and Molecular Genetics, University of Alabama, Birmingham, AL, USA 2: Department of Biochemistry and Molecular Genetics, University of Alabama, Birmingham, AL, USA, Department of Neurobiology, University of Alabama, Birmingham, AL, USA

Publication date: 2005-03-01

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The Molecular and Cellular Biology area of Gene Expression covers all aspects of the gene including it structure, functions, and regulation in prokaryotes, eukaryotes, and viruses; molecular and cell biological aspects of cell growth and development, chromatin structure and function. These include topics such as DNA replication, DNA repair, gene transcription, transcriptional control, RNA processing, posttranscriptional control, oncogenes, molecular mechanisms of action of hormones, molecular mechanism of cellular differentiation, growth and development, protein synthesis, and posttranslational control.
The Molecular and Cellular Neuroscience area of Gene Expression covers all aspects of gene expression as described but is devoted exclusively to the nervous system in health and disease. Topics include studies of neurogenesis, development, aging, and neurodegeneration. Complex neural systems, motor control, special senses, and higher cortical function, when viewed from the perspective of gene expression, are appropriate for the journal. Research related to molecular mechanisms of drug tolerance, dependence, and withdrawal are solicited. Manuscripts on state-of-the-art methods and protocols for molecular profiling of neuronal structure and function are welcome.

Allele-Specific Conditional Destabilization of Glutamine Repeat mRNAs

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