Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 9, Pages 3467-3472Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0800048105
Keywords
CAG repeat instability; differentiated neuron; Huntington's disease; mismatch repair; somatic mutation
Categories
Funding
- Medical Research Council [G9800001] Funding Source: Medline
- Wellcome Trust [60360, 66270] Funding Source: Medline
- Medical Research Council [G9800001] Funding Source: researchfish
- MRC [G9800001] Funding Source: UKRI
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Huntington's disease (HD) is caused by a CAG repeat expansion that is unstable upon germ-line transmission and exhibits mosaicism in somatic tissues. We show that region-specific CAG repeat mosaicism profiles are conserved between several mouse models of HD and therefore develop in a predetermined manner. Furthermore, we demonstrate that these synchronous, radical changes in CAG repeat size occur in terminally differentiated neurons. In HD this ongoing mutation of the repeat continuously generates genetically distinct neuronal populations in the adult brain of mouse models and HD patients. The neuronal population of the striatum is particularly distinguished by a high rate of CAG repeat allele instability and expression driving the repeat upwards and would be expected to enhance its toxicity. In both mice and humans, neurons are distinguished from nonneuronal cells by expression of MSH3, which provides a permissive environment for genetic instability independent of pathology. The neuronal mutations described here accumulate to generate genetically discrete populations of cells in the absence of selection. This is in contrast to the traditional view in which genetically discrete cellular populations are generated by the sequence of random variation, selection, and clonal proliferation. We are unaware of any previous demonstration that mutations can occur in terminally differentiated neurons and provide a proof of principle that, dependent on a specific set of conditions, functional DNA polymorphisms can be produced in adult neurons.
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