Team Doxakis

Parkinson’s disease exhibits substantial clinical heterogeneity driven in part by co-aggregation of α synuclein, tau, and TDP43 proteins. This proposal investigates how chronic cellular stress reduces membraneless organelle fluidity through altered liquid-liquid phase separation, trapping RNA-binding proteins and disrupting transcription, splicing, and proteostasis. These perturbations create synergistic protein aggregation that accelerates neurodegeneration along vulnerable midbrain-cortical circuits. Using iPSC-derived midbrain assembloids, transgenic rats, and stratified human brain samples, the study will define molecular mechanisms underlying co-pathology formation, identify quantitative signatures predicting disease progression, and validate therapeutic targets for treating PD heterogeneity.