Huntington's disease: Silencing a brutal killer

Abstract

Huntington’s disease (HD) is a progressive and invariably fatal autosomal dominant neurodegenerative disorder caused by expansion of the CAG repeat in exon 1 of the Huntingtin gene. CAG repeat expansion generates an extended, toxic polyglutamine tract in the mutant Huntingtin protein (The Huntington’s Disease Collaborative Research Group, 1993), which disrupts a stunningly large number of cellular pathways. Mutant Huntingtin is especially damaging to the medium spiny neurons of the striatum (Graveland et al., 1985), and degeneration in this region is thought to underlie the motor disturbances or —chorea that characterize the disease. In parallel, loss of striatal and cortical neurons disrupts patient cognition and alters mood and personality (Heinsen et al., 1994). The age of onset of HD varies with CAG repeat length (Brinkman et al., 1997; Duyao et al., 1993) 36 or more repeats is considered pathological, but some patients with 36 to 39 repeats remain asymptomatic well into old age. The vast majority of patients are heterozygous for the HD mutation; most have 39 to 50 repeats and develop symptoms between age 30 and 50. No current treatment can prevent or delay the progression of HD.