Aggregation in Huntington's disease: insights through modelling.

Abstract

Huntington's Disease (HD) is a late-onset, progressively degenerative brain disorder characterized by cell loss in the striatum and cortex. HD is caused by a polyglutamine (polyQ) expansion in the protein huntingtin (Htt). The mutant Htt is a substrate for caspases -2, -3 and -6. The cleavage of mutant Htt by caspase-2 has been suggested to underlie the selective neuronal death in HD. Once the mutant Htt is cleaved, a sticky and toxic fragment with the potential to form aggregates is released. The role of aggregation in the progression of HD has been extensively studied, yielding a plethora of ambivalent results. It has been shown that these are the diffuse, monomeric and oligomeric, forms of the mutant Htt fragment rather than the aggregates that are the major source of toxicity to the cells. We present here a mathematical model for aggregation in HD and discuss how it can relate to the selective neuronal death and the dependence of the disease onset on polyQ length. We describe the dynamical behavior of caspase-2, the release of monomeric forms of the mutant Htt fragment and the aggregation of these fragments through intermediate steps. Our model predicts that the concentration of toxic, intermediate oligomeric structures does not increase with increased caspase activity. We therefore suggest that the intermediate oligomeric forms of toxic Htt fragment do not account for selective and polyQ dependent neuronal death.