Higher-Order Adaptive Dynamical System Modeling of the Role of Epigenetics in Huntington’s Disease

This paper introduces a fifth-order adaptive dynamical system model to analyse the epigenetic mechanisms linking environmental stressors to the progression of Huntington’s disease (HD). Environmental stressors induce DNA methylation of brain-derived neurotrophic factor (BDNF), a protein essential for neuronal survival and synaptic function. The model explores how methylation of the BDNF promoter interacts with epigenetic dysregulation caused by the mutant huntingtin protein, initiating a cascade from molecular changes to clinical symptoms. Multiple orders of adaptivity are used to represent these biological control levels, where higher-order processes control and modulate lower-order pathways. Simulation experiments demonstrate two key findings: first, that chronic stress accelerates symptom development by suppressing BDNF expression; and second, that a simulated epigenetic therapy targeting DNA methylation successfully ameliorates disease symptoms. By providing a comprehensive framework for the interplay between genetics, environment, and epigenetic control, this work offers insights into disease variability and supports the development of novel therapeutic strategies targeting epigenetic pathways in HD.