Disease-linked mutations dysregulate neuronal condensate physical properties, composition, and RNA translation

Local RNA translation is essential for development. In neurons, deficient local translation linked with mutations in scaffold proteins results in dysregulated dendrite and dendritic spine growth. However, mechanisms by which these proteins control translation and how disease-linked mutations induce aberrant translation were unclear. We use biochemical reconstitution and neuronal assays to show that mutations to the neuronal condensate scaffold shank2 cause physical hardening and altered composition of condensates; a key RNA translation-modulator FMRP is excluded from mutant condensates. Functionally, shank2 condensates repress translation while condensates composed of shank2 with intrinsically disordered region-localized missense mutations promote translation. These results demonstrate that disease-linked dysregulation of condensate physical properties and composition is an underlying mechanism of aberrant RNA translation often observed in disease. One Sentence SummaryDisease-linked missense mutations in the postsynaptic density scaffold protein shank2 dysregulate phase separated biomolecular condensate physical properties and composition resulting in aberrant RNA translation.