HD Blog

Pathologic allelic variants: The mutation underlying HD is an expansion of a CAG/polyglutamine tract in the first exon [HDCRG 1993]. The CAG repeat length in patients with HD ranges from 36 to 121 (median 40). Adult-onset patients usually have an expansion from 40 to 55, whereas juvenile-onset patients have expansions above 50 that are often inherited from the father. A well-established inverse correlation between CAG repeat length and age of onset exists [Brinkman et al 1997]. However, penetrance in the repeat range of 36 - 41 is reduced.

Normal gene product: Huntingtin. The HD gene lacks homology to any previously characterized gene and encodes a protein (huntingtin) of 3144 amino acids with a predicted molecular mass of 348 kDa. Huntingtin is widely expressed with no obvious differences in the regional distribution of the mutant and wild type protein. The polyglutamine tract starts at residue 18 and is followed by a polyproline region. The region downstream of the polyglutamine tract contains a HEAT repeat, a motif that consists of 40 loosely conserved amino acids repeated multiple times in tandem, which is proposed to be involved in protein-protein interactions [Andrade & Bork 1995].

Abnormal gene product: The CAG in the HD gene is translated into an uninterrupted stretch of glutamine residues which when expanded may have altered structural and biochemical properties. Several models to explain the pathogenesis of CAG expansion diseases have focused on the structural and biochemical properties of long glutamine tracts. Polyglutamine stretches are potential substrates for transglutaminases which may crosslink glutamines in the tract with lysine residues in other proteins, leading to the formation of protease resistant glutamyl-lysyl cross-links and isopeptides [Green 1993]. However, such cross-linked isopeptides have not been demonstrated in neurons that degenerate in HD. Polyglutamine stretches tend to form polar zippers and aggregate together via hydrogen bonding [Perutz et al 1994 , Perutz 1994 , Stott et al 1995]. Protein-protein interactions mediated by polyglutamine tracts might simply result in insoluble and toxic precipitates, analogous to the aggregates such as amyloid deposits implicated in the pathogenesis of other neurodegenerative diseases. Proteolytic cleavage of a GST-huntingtin fusion amyloid-like protein results in protein aggregates when the polyglutamine expansion is in the pathogenic range [Scherzinger et al 1997]. Similar aggregates have been found in HD brains, the brains of mice transgenic for exon 1 of the human HD gene carrying 115 to 156 CAG repeat expansions [Scherzinger et al 1997 , DiFiglia et al 1997], and in cultured cells transfected with HD expression constructs [Martindale et al 1998 , Cooper et al 1998 , Hackam et al 1998].

Interacting Proteins
A number of interacting proteins, including HAP-1 and HIP1, in which interaction is altered when the polyglutamine repeat is expanded, have been identified. Their role in selective neuronal loss in HD has not yet been determined. Huntingtin has recently been demonstrated to be a substrate for caspase-3, whose action results in the formation of a smaller product. There is accumulating evidence that aminoterminal fragments of huntingtin containing expanded polyglutamine tracts may be toxic to cells [Martindale et al 1998 , Hackam et al 1998].

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