It has been 20 y since the gene responsible for Huntington disease—a fatal neurodegenerative disorder—was identified by an intensive international collaborative effort (1). Although the features of the gene offered few clues to its normal function, the cloning of the IT15 gene immediately provided insight into the mechanism underlying disease: expansion of a CAG trinucleotide repeat within the first exon of the gene, which encodes a polyglutamine stretch in the huntingtin protein, was found to correlate with the onset of Huntington disease and the autosomal dominant mode of inheritance. At the time, this was a relatively novel observation, with the first example of a polyglutamine-encoding CAG repeat disease—spinal and bulbar muscular atrophy (Kennedy disease)—having been uncovered just 2 y prior (2). These diseases were the initial members of a group of at least nine polyglutamine-based neurodegenerative disorders that have been subsequently described (3). Interestingly, many of these diseases exhibit a similar critical polyglutamine length threshold that leads to pathogenesis (4). In the case of Huntington disease, alleles with a repeat size of 40 or greater are completely penetrant, whereas alleles with 36–39 repeats are incompletely penetrant (5), with genetic and environmental factors likely contributing to this variation. Amino-terminal fragments of huntingtin with expanded polyglutamine stretches misfold and form aggregates in vitro and in brains of Huntington patients (6, 7). A great deal of research supports the notion that misfolding/aggregation of huntingtin leads to a “toxic gain-of-function” mechanism at the root of disease pathogenesis, although loss of endogenous huntingtin function (8) and RNA-based toxicity (9) may also play a role in Huntington disease. A caveat of many of the gain-of-function studies is that extremely expanded … [↵][1]1E-mail: fg36{at}le.ac.uk. [1]: #xref-corresp-1-1
