CAG expansion affects the expression of mutant huntingtin in the Huntington's disease brain

Abstract

A trinucleotide repeat (CAG) expansion in the huntingtin gene causes Huntington's disease (HD). In brain tissue from HD heterozygotes with adult onset and more clinically severe juvenile onset, where the largest expansions occur, a mutant protein of equivalent intensity to wild-type huntingtin was detected in cortical synaptosomes, indicating that a mutant species is synthesized and transported with the normal protein to nerve endings. The increased size of mutant huntingtin relative to the wild type was highly correlated with CAG repeat expansion, thereby linking an altered electrophoretic mobility of the mutant protein to its abnormal function. Mutant huntingtin appeared in gray and white matter with no difference in expression in affected regions. The mutant protein was broader than the wild type and in 6 of 11 juvenile cases resolved as a complex of bands, consistent with evidence at the DNA level for somatic mosaicism. Thus, HD pathogenesis results from a gain of function by an aberrant protein that is widely expressed in brain and is harmful only to some neurons.

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

“…Also noteworthy is the Huntington's disease region that, in addition to containing one Alu pair that met the above criterion, also had more Alu pairs that had similar features. This region also contains a multiple trinucleotide repeat at-risk DNA motif (Aronin et al 1995), however, this does not exclude the possibility of another risk factor.…”

Subcellular and Subsynaptic Localization of Presynaptic and Postsynaptic Kainate Receptor Subunits in the Monkey Striatum

“…In Ͼ60% of HD patients, increasing length of CAG repeats correlates highly with a decrease in the age of onset of the disease or the extent of striatal degeneration (Persichetti et al, 1994;Aronin et al, 1995;Penney et al, 1997). However, recent findings have reported that the variance in the age of onset of HD could also be attributed to mutations in the gene encoding the GluR6 KAR subunit (Rubinsztein et al, 1997;MacDonald et al, 1999).…”

Analysis of the CAG Repeat Number in a Patient with Huntington's Disease.

“…Somatic heterogeneity is thought to result in the translation of multiple mutant Huntingtin protein products. Actually, Aronin et al ( 15) reported the existence of somatic mosaicismof Huntingtin protein in brains from HDpatients, and established that the increased size of mutant Huntingtin relative to the wild type was highly correlated with CAGrepeat expansion. The fact that the mosaicism of the mutant protein was found to be more prominent in more pathologically affected brain regions, and that the mosaicism of the mutant protein was found to be greater injuvenile cases than in adult onset cases, is very muchin line with the triplet CAGanalysis.…”

“…Tissuespecific somatic mosaicismmight be the result of the alteration of cell population related to selective survival and lost neuronal groups in addition to the glial response in certain CNS regions. It was reported that glial cells clearly manifest a high degree of repeat instability (6,15). Some authors have hypothesized that neuronal degeneration and subsequent gliosis could give rise to the somatic mosaicism at both the DNAand protein level (15).…”

“…It was reported that glial cells clearly manifest a high degree of repeat instability (6,15). Some authors have hypothesized that neuronal degeneration and subsequent gliosis could give rise to the somatic mosaicism at both the DNAand protein level (15). If this is the case, somatic mosaicism may directly correspond to region-specific neuronal degeneration.…”