title: One-hit stochastic decline in a mechanochemical model of cytoskeleton-induced neuron death II: transition state metastability.
abstract: This is the second of two papers in which we study a mathematical model of cytoskeleton-induced neuron death. Recent evidence indicates that aggravated assembly or destruction of the cytoskeleton can trigger programmed death in neurons, by mechanisms as yet poorly understood. In our model, assembly control of the neuronal cytoskeleton interacts with both cellular stress levels and cytosolic free radical concentrations to trigger neurodegeneration. This trigger mechanism is further modulated by a diffusible toxic factor released from dying neurons. In the companion report we established that the model relates the observed general patterns of neuron decline to specific scales of cytoskeleton reorganization and cell-cell interaction strength. In this paper we study the transit of neurons through states intermediate between initial viability and cell death in our model. We find that the stochastic flow of neuron fate, from viability to cell death, self-organizes into two distinct temporal phases. There is a rapid relaxation of the initial neuron population to a more disordered phase that is long-lived, or metastable, with respect to the time scales of change in single cells. Strikingly, cellular egress from this metastable phase follows the one-hit kinetic pattern of exponential decline now established as a principal hallmark of cell death in neurodegenerative disorders. Intermediate state metastability may therefore be an important element in the systems biology of one-hit neurodegeneration.
authors.affiliation: Institute of Medical Science and Department of Medicine, University of Toronto, Room 7313, Medical Science Building, University of Toronto, 1 Kings College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lomasko
authors.forename: Geoff
authors.initials: G
authors.lastname: Clarke
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lumsden
mesh_terms: D001696:Biomechanical Phenomena; D016923:Cell Death / Q000502:physiology; D003198:Computer Simulation; D003599:Cytoskeleton / Q000473:pathology*; D006801:Humans; D008959:Models, Neurological; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D013269:Stochastic Processes