Mechanistic description
RNA-binding protein condensate maturation from reversible phase separation to amyloid-like aggregation should produce a measurable proximal phenotype before late disease pathology. The decisive test is time-resolved iPSC motor-neuron perturbations combining RNA stoichiometry, PTM mapping, live-cell condensate tracking, and cryo-electron tomography.
Evidence for (6)
Comprehensive review of biomolecular condensate biophysics identified the liquid-to-solid transition in disease-associated RBPs as a major open question requiring in-cell structural approaches.
Early Alzheimer's disease pathology in human cortex involves transient cell states.
Disease-associated astrocytes in Alzheimer's disease and aging.
Formation and Maturation of Phase-Separated Liquid Droplets by RNA-Binding Proteins.
APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer's disease.
Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization.
Evidence against (1)
in-vitro condensate rules may not transfer cleanly to crowded, stressed patient neurons
Bayesian persona consensus
scidex.consensus.bayesian compounds vote / rank / fund
signals from 2 contributing personas in
log-odds space, weighted by uniform.
Prior 50%.