Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans

Mutation of the Wiskott–Aldrich syndrome protein and SCAR homology (WASH) complex subunit, SWIP, is implicated in human intellectual disability, but the cellular etiology of this association is unknown. We identify the neuronal WASH complex proteome, revealing a network of endosomal proteins. To uncover how dysfunction of endosomal SWIP leads to disease, we generate a mouse model of the human WASHC4(c.3056C>G) mutation. Quantitative spatial proteomics analysis of SWIP(P1019R) mouse brain reveals that this mutation destabilizes the WASH complex and uncovers significant perturbations in both endosomal and lysosomal pathways. Cellular and histological analyses confirm that SWIP(P1019R) results in endo-lysosomal disruption and uncover indicators of neurodegeneration. We find that SWIP(P1019R) not only impacts cognition, but also causes significant progressive motor deficits in mice. A retrospective analysis of SWIP(P1019R) patients reveals similar movement deficits in humans. Combined, these findings support the model that WASH complex destabilization, resulting from SWIP(P1019R), drives cognitive and motor impairments via endo-lysosomal dysfunction in the brain.