Addivosome

A central challenge of separating pathological from physiological condensates can be addressed by targeting state-specific features rather than core scaffold proteins.

The proposed pathological condensate state enforces aberrant pathway cross-talk, biases gene regulation, and resists dispersal, creating a durable cellular mnemonic.

Repeated cycles of intoxication, withdrawal, and abstinence progressively shift the postsynaptic density toward a more rigid, self-maintaining state through co-activation of dopamine and glutamate pathways.

The paper proposes that persistent relapse vulnerability in addiction arises when the postsynaptic density pathologically matures into a maladaptive phase-separated condensate termed the Addivosome.

Compounds can be screened for restoration of liquid-like molecular mobility, or reliquefaction, using fluorescence recovery after photobleaching as the readout.

Optogenetic tools that acutely cluster or disperse selected synaptic proteins are proposed to establish causality in the Addivosome model.

Proximity labeling is proposed to define state-specific proteomic and post-translational signatures for evaluating the Addivosome model.

Selective clearance of the pathological condensate is proposed using autophagy-tethering chimeras directed at drug-induced signatures.