Article

Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain

Department of Psychiatry, Columbia University, New York, New York, United States
Human Molecular Genetics (Impact Factor: 6.39). 06/2007; 16(10):1133-42. DOI: 10.1093/hmg/ddm054
Source: PubMed

ABSTRACT

Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Here, we provide evidence supporting the hypothesis that somatic increases of mutation length play a role in the progressive nature and cell-selective aspects of HD pathogenesis. Results from micro-dissected tissue and individual laser-dissected cells obtained from human HD cases and knock-in HD mice indicate that the CAG repeat is unstable in all cell types tested although neurons tend to have longer mutation length gains than glia. Mutation length gains occur early in the disease process and continue to accumulate as the disease progresses. In keeping with observed patterns of cell loss, neuronal mutation length gains tend to be more prominent in the striatum than in the cortex of low-grade human HD cases, less so in more advanced cases. Interestingly, neuronal sub-populations of HD mice appear to have different propensities for mutation length gains; in particular, smaller mutation length gains occur in nitric oxide synthase-positive striatal interneurons (a relatively spared cell type in HD) compared with the pan-striatal neuronal population. More generally, the data demonstrate that neuronal changes in HD repeat length can be at least as great, if not greater, than those observed in the germline. The fact that significant CAG repeat length gains occur in non-replicating cells also argues that processes such as inappropriate mismatch repair rather than DNA replication are involved in generating mutation instability in HD brain tissue.

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    • "The degree of intergenerational CAG expansion is dependent on the sex of the affected parent, with large expansions occurring in the male germline and small contractions occurring in the female germline [4,5]. Interestingly, the length of the Htt CAG repeat has been shown to be dramatically increased in HD brains, particularly in affected regions such as the striatum [6,7]. Despite almost 2 decades of research, the normal function of the Htt protein and the pathogenesis of mutant Htt are not fully understood. "
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    • "Huntington's disease (HD) is an inherited neurodegenerative disorder that originates from a polyglutamine repeat expansion in the native huntingtin protein. Mutant huntingtin (mHtt) causes abnormal protein aggregation that leads to chorea, dyskinesia, neural cell loss, and eventually death (Andrew et al., 1993; Shelbourne et al., 2007). Although degeneration and atrophy occur in multiple brain regions in HD, the cortex and caudate nucleus of the striatum are the most notably impacted. "
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    • "[24] [25] [26] [27]). Expansions have been observed in non-dividing cells in affected humans including neurons of patients with Huntington disease (HD) [28] [29], Dentatorubral–pallidoluysian atrophy (DRPLA) [30] and Friedreich ataxia (FRDA) [31]. Expansions are also seen in the oocytes of women with myotonic dystrophy type 1 (DM1) [32] [33] and a maternal age effect is seen on the transmission of expanded alleles in DM1, fragile X syndrome (FXS) and FRDA [13] [34] [35]. "
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