The effect of neuronal atrophy on the pathogenesis of Huntington's disease.

Abstract

Computational models play a pivotal role in the integration of complex biochemical reaction kinetics with the subcellular organization to obtain a deeper understanding of the cellular response to a drug. We have created a realistic 3D reconstruction of a segment of the axon including the endoplasmic reticulum and the subcellular arrangement of molecules involved in calcium homeostasis and calcium-induced calcium release. The dynamics of the system are modeled using MCell4, a stochastic, particle-based Monte Carlo simulator. We studied the effect of cell atrophy on the disease state of Huntington's disease (HD), a fatal neurological disorder that has no cure yet. HD is characterized by motor dysfunction, mental impairment, and cognitive decline. At the molecular level, HD is caused by a mutation in the first exon of the gene encoding the Huntingtin protein resulting in an expanded polyglutamine. Calcium dyshomeostasis is believed to be one of the key causes of HD. In particular, defective RyR function has been reported in HD leading to elevated intracellular Ca2+ levels. One of the drugs currently under development that can potentially be used for HD is a small-molecule drug RycalTM that may act by stabilizing leaky ryanodine receptor (RyR)/Ca2+ release channels that are in development for a severe form of muscle atrophy. Interestingly, our model indicates that even if all receptors and calcium pumps work normally, cell atrophy alone could lead to the “leaky RyR” receptors phenomenon, and will further result in saturation of the calcium buffer, calbindin, and accumulation of intercellular calcium which can be quite toxic to the cell. The computer model that we have built can be further developed to help us understand whether drugs in development or proposed for HD might be worthwhile or not in an effort to treat/cure HD.