Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans.
| dc.contributor.author | Courtland, Jamie L | |
| dc.contributor.author | Bradshaw, Tyler Wa | |
| dc.contributor.author | Waitt, Greg | |
| dc.contributor.author | Soderblom, Erik J | |
| dc.contributor.author | Ho, Tricia | |
| dc.contributor.author | Rajab, Anna | |
| dc.contributor.author | Vancini, Ricardo | |
| dc.contributor.author | Kim, Il Hwan | |
| dc.contributor.author | Soderling, Scott H | |
| dc.date.accessioned | 2022-08-22T18:36:15Z | |
| dc.date.available | 2022-08-22T18:36:15Z | |
| dc.date.issued | 2021-03-22 | |
| dc.date.updated | 2022-08-22T18:36:03Z | |
| dc.description.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. | |
| dc.identifier | 61590 | |
| dc.identifier.issn | 2050-084X | |
| dc.identifier.issn | 2050-084X | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.publisher | eLife Sciences Publications, Ltd | |
| dc.relation.ispartof | eLife | |
| dc.relation.isversionof | 10.7554/elife.61590 | |
| dc.subject | Endosomes | |
| dc.subject | Lysosomes | |
| dc.subject | Animals | |
| dc.subject | Mice, Transgenic | |
| dc.subject | Humans | |
| dc.subject | Mice | |
| dc.subject | Movement Disorders | |
| dc.subject | Intracellular Signaling Peptides and Proteins | |
| dc.subject | Proteome | |
| dc.subject | Cognition | |
| dc.subject | Movement | |
| dc.subject | Female | |
| dc.subject | Male | |
| dc.subject | Intellectual Disability | |
| dc.title | Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans. | |
| dc.type | Journal article | |
| duke.contributor.orcid | Courtland, Jamie L|0000-0001-6846-3552 | |
| pubs.begin-page | e61590 | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Staff | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Cell Biology | |
| pubs.organisational-group | Neurobiology | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.organisational-group | Institutes and Provost's Academic Units | |
| pubs.organisational-group | University Institutes and Centers | |
| pubs.organisational-group | Duke Institute for Brain Sciences | |
| pubs.publication-status | Published | |
| pubs.volume | 10 |
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