Aggregation inhibitors: hope for Huntington’s?

Abstract

Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disease that affects 3–4 in every 10 000 Caucasians. Its symptoms include the involuntary movements that gave rise to its old name of Huntington’s chorea, and it leads to increasing disability and death within 10–15 years. The genetic defect that causes this devastating disease is an expanded CAG repeat in a gene encoding a protein of unknown function known as huntingtin. Unaffected individuals have fewer than 35 CAG repeats in exon 1 of this gene; individuals affected by HD have between 37 and 120 such repeats. As this mutation is in a coding region, the affected protein contains an expanded polyglutamine (polyQ) tract. The number of glutamines is one of several factors that determines the age of onset of the disease. In an introductory lecture at the FEBS meeting, Jean-Louise Mandel (Université Louis Pasteur, Illkirch, France) explained: ‘Every extra glutamine takes 18 months off the average age of onset of Huntington’s symptoms’. Several other neurological conditions are known to be associated with expanded polyQ repeats in proteins. The disease-causing threshold of 35–40 glutamines seen in HD is typical of this type of disease.