Huntingtin and the molecular pathogenesis of Huntington's disease

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Abstract
Huntington's disease (HD) is a late‐onset neurodegenerative disorder that is caused by a CAG repeat expansion in the IT15 gene, which results in a long stretch of polyglutamine close to the amino‐terminus of the HD protein huntingtin (htt). The normal function of htt, and the molecular mechanisms that contribute to the disease pathogenesis, are in the process of being elucidated. In this review, we outline the potential functions of htt as defined by the proteins with which it has been found to interact. We then focus on evidence that supports a role for transcriptional dysfunction and impaired protein folding and degradation as early events in disease pathogenesis. Huntington's disease (HD) is an autosomal‐dominant disorder characterized by irrepressible motor dysfunction, cognitive decline and psychiatric disturbances, which lead to progressive dementia and death approximately 15–20 years after disease onset (Bates et al , 2002). It belongs to a family of neurodegenerative diseases caused by mutations in which an expanded CAG repeat tract results in long stretches of polyglutamine (polyQ) in the encoded protein. This family also includes dentatorubral‐pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA) and the spinocerebellar ataxias (SCAs) 1–3, 6, 7 and 17. Apart from their polyQ repeats, the proteins involved are unrelated, and although they are all widely expressed in the central nervous system and peripheral tissues, they lead to characteristic patterns of neurodegeneration. In HD, the selective neurodegeneration of the γ‐aminobutyric acid‐releasing spiny‐projection neurons of the striatum is predominant, although loss of neurons in many other brain regions has also been reported. In the unaffected population, the number of CAG repeats in the IT15 gene that encodes the HD protein huntingtin (htt) varies from 6 to 35; repeats of 36 or more define an HD allele. The length of the CAG expansion is inversely correlated with age of …