Misfolded protein propagation in an integrated computational model of structural network and LRRK2 gene expression

It has been widely accepted that Parkinson's disease (PD) is triggered and shaped by propagation of misfolded α-synuclein. Converging neurophysiological evidence suggests that leucine-rich repeat kinase 2 (LRRK2) is involved in membrane transport of PD pathogenesis. This study proposed an agent-based computational model by integrating structural connections and gene expression to investigate whether LRRK2 would affect the PD pathology propagation in central nervous system. Gene expression profiles from the Allen Human Brain Atlas (AHBA) and multimodal brain MRI images from Parkinson's Progression Markers Initiative (PPMI) and Human Connectome Project (HCP) were employed for the model construction. The model results exhibit the involvement of LRRK2 gene expression remarkably elevated model fitting (r = 0.73) compared with the traditional susceptible-infected-removed (S-I-R) model (r=0.60). Specifically, our model revealed that LRRK2 is more likely to modulate pathology secretion out of neurons, rather than spreading into neurons. The findings support the theory of LRRK2 gene expression modulating cell-to-cell propagation of misfolded proteins. As a result, the proposed model would bring new insights of understanding PD mechanism in terms of misfolded α-synuclein propagation.