How repair-or-dispose decisions under stress can initiate disease progression

Abstract

Glia, the helper cells of the brain, are essential in maintaining neural resilience across time and varying challenges: By reacting to changes in neuronal health glia carefully balance repair or disposal of injured neurons to prevent further tissue damage. Malfunction of these interactions is implicated in many neurodegenerative diseases. Reductionist models with a minimal number of parameters provide the opportunity to gain insight into biological functions and inform experimental designs. We introduce such a model that mimics long-term implications of repair-or-dispose decisions. Depending on the functionality of the decision-making process, the model assumes four distinct tissue states: healthy, challenged, primed tissue at risk of acute damage propagation, and chronic neurodegeneration. These states of the model correspond to the progression stages observed in the most common neurodegenerative conditions. The underlying mechanisms are in agreement with experimental observations of glia-neuron crosstalk and reproduce a homeostatic balance between repairing and damage-inducing reactions. The model suggests that the onset of neurodegeneration results from a tug-of-war between two conflicting goals: short-term resilience to stressors vs long-term prevention of tissue damage.