Programmable self-assembling system to model intracellular protein aggregation and decode neurodegenerative diseases

Pathological protein aggregation is a conserved feature of neurodegenerative diseases. However, slow progression, aggregates heterogeneity and selective vulnerability make it challenging to model diseases and dissect mechanisms. Here, we present a genetically-encoded, modular platform of self-assembling protein that enables inducible, tunable and cell-type-specific formation of intracellular protein aggregates. We engineered self-assembling variants of -synuclein (SAS), Tau, and TDP-43, recapitulating hallmarks of Parkinsons disease, Alzheimers disease, and ALS, respectively. SAS formed Lewy body-like inclusions, nucleated endogenous -synuclein, triggered neuroinflammation and neurite degeneration; Self-assembling-Tau induced tangles formation, extracellular A{beta} and severe neurodegeneration; Self-assembling-TDP caused TDP-43 mislocalization and cytoplasmic inclusions with mild degeneration. Notably, the system revealed disease-specific aggregate-organelle interactions. In vivo, systemic or dopamine neuron-targeted delivery of SAS induced progressive motor deficits, dopaminergic neuron loss, and microglial activation. Our self-assembling system robustly mirrors histological, transcriptional, and behavioral features of human disease, providing a powerful platform to dissect mechanisms and accelerate therapeutic development. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/641009v2_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1906bb2org.highwire.dtl.DTLVardef@8e8141org.highwire.dtl.DTLVardef@1c7e62dorg.highwire.dtl.DTLVardef@d8c05a_HPS_FORMAT_FIGEXP M_FIG C_FIG