In silico reconstructions underpin aberrant trafficking dynamics in deficient axons of Dst knockout and Dst/Nefl double-knockout mice.

Abstract

Aberrant neuronal trafficking is a significant hallmark of neurodegenerative pathology. Its real-time evolution remains elusive and poorly defined due to the lack of a predictive spatiotemporal framework. Building upon a general neurocytoskeletal-PDEs (iGCPs) model, we propose the concept of Virtual Cellular Dynamics for quantitative spatiotemporal simulations of mitochondrial dynamics within axons. The model integrates interactions of key cytoskeletal components such as dystonin, microtubule, neurofilament, and actin filament, providing a comprehensive framework for neuron-specific virtual cell modeling, enabling quantitative insight into axonal dysfunction and structural degradation across neurodegenerative disease. Not only does our model recapitulate the significant structural deformations and mitochondrial transport disruptions observed in Dst-deficient mice, but it further predicts that the ablation of Nefl alleviates severe neurodegenerative progression-a finding substantiated by multi-modal imaging and Dst/Nefl double-knockout murine models, which reveal phenotypic rescue and validate the potential of NF-L-targeted therapeutic strategies. Altogether, our work paves the way for next-generation virtual cell models tailored to neuron-specific disease states.