Progressive Remodeling of Global Protein Interaction Networks in a Mouse Model of Tauopathy.

Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present the first temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating co-fractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This interactomic atlas identifies functionally validated assemblies-including MAPT-Dpysl2 and Cyfip1-actin complexes-that modulate early disease phenotypes in vivo. By revealing how phosphorylation tunes macromolecular complex architecture and function, this work reframes tauopathy as a disease of dynamic network instability, and establishes a generalizable framework for early detection and mechanistic dissection of neurodegeneration.