Protein-protein interactions in neurodegenerative diseases: A conspiracy theory

Abstract

Neurodegenerative diseases such as Alzheimer’s or Parkinson’s are associated with the prion-like propagation and aggregation of toxic proteins. A long standing hypothesis that amyloid-beta drives Alzheimer’s disease has proven the subject of contemporary controversy; leading to new research in both the role of tau protein and its interaction with amyloid-beta. Conversely, recent work in mathematical modeling has demonstrated the relevance of nonlinear reaction-diffusion type equations to capture essential features of the disease. Such approaches have been further simplified, to network-based models, and offer researchers a powerful set of computationally tractable tools with which to investigate neurodegenerative disease dynamics. Here, we propose a novel, coupled network-based model for a two-protein system that includes an enzymatic interaction term alongside a simple model of aggregate transneuronal damage. We apply this theoretical model to test the possible interactions between tau proteins and amyloid-beta and study the resulting coupled behavior between toxic protein clearance and proteopathic phenomenology. Our analysis reveals ways in which amyloid-beta and tau proteins may conspire with each other to enhance the nucleation and propagation of different diseases, thus shedding new light on the importance of protein clearance and protein interaction mechanisms in prion-like models of neurodegenerative disease.