mutations in Huntington disease
Pathogenesis
Amyloid and huntingtin
Huntington disease results from the aggregation of the neuronal protein huntingtin. Compared with the other conformational dementias, the appearance of intracellular inclusions is a late feature of the disease. The reason for this is that the initial aggregates are efficiently removed by cellular chaperones and it is only when these become overwhelmed, after many years, that the aggregates develop and with them the clinical manifestations.
The cause of the aggregation is the presence in the tail of the huntingtin molecule of a large glutamine-repeat domain that can undergo an inheritable extension. If the size of this domain extends beyond 37 repeats, then intermolecular bonding between tails forms the aggregates.
An intriguing explanation for the beta-linked structure of the huntingtin aggregates, which has wider implications for amyloids in general, has recently been proposed.
This model suggests that the glutamine repeats form a cylindrical sheet made up of beta-strands with 20 residues per helical turn, and provides a satisfying hypothesis for the crucial threshold of 37-40 glutamine repeats that are required for neurodegeneration in Huntington disease.
A single turn with 20 residues would be unstable, as there is nothing to hold it in place; however, 2 turns with 40 residues are stabilized by the hydrogen bonds between their amides, and such initial 2-turn structures can then act as nuclei for further helical growth.
References
Li SH, Li XJ. Huntingtin-protein interactions and the pathogenesis of Huntington's disease. Trends Genet. 2004 Mar;20(3):146-54. PMID: #15036808#
Lomas DA, Carrell RW. Serpinopathies and the conformational dementias. Nat Rev Genet. 2002 Oct;3(10):759-68. PMID: #12360234#