Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans.
Abstract
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 WASHC4c.3056C>G mutation. Quantitative
spatial proteomics analysis of SWIPP1019R 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 SWIPP1019R results in endo-lysosomal
disruption and uncover indicators of neurodegeneration. We find that SWIPP1019R not
only impacts cognition, but also causes significant progressive motor deficits in
mice. A retrospective analysis of SWIPP1019R patients reveals similar movement deficits
in humans. Combined, these findings support the model that WASH complex destabilization,
resulting from SWIPP1019R, drives cognitive and motor impairments via endo-lysosomal
dysfunction in the brain.
Type
Journal articleSubject
EndosomesLysosomes
Animals
Mice, Transgenic
Humans
Mice
Movement Disorders
Intracellular Signaling Peptides and Proteins
Proteome
Cognition
Movement
Female
Male
Intellectual Disability
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https://hdl.handle.net/10161/25597Published Version (Please cite this version)
10.7554/elife.61590Publication Info
Courtland, Jamie L; Bradshaw, Tyler Wa; Waitt, Greg; Soderblom, Erik J; Ho, Tricia;
Rajab, Anna; ... Soderling, Scott H (2021). Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement
impairments in mice and humans. eLife, 10. pp. e61590. 10.7554/elife.61590. Retrieved from https://hdl.handle.net/10161/25597.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Erik James Soderblom
Associate Research Professor of Cell Biology
Director, Proteomics and Metabolomics Core Facility
Scott Haydn Soderling
George Barth Geller Distinguished Professor of Molecular Biology
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