Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization
Romano, Lisa E. L., Aw, Wen Yih, Hixson, Kathryn M., Novoselova, Tatiana 
ORCID: https://orcid.org/0000-0002-2394-4667, Havener, Tammy M., Howell, Stefanie, Taylor-Blake, Bonnie, Hall, Charlotte L., Xing, Lei, Beri, Josh, Nethisinghe, Suran, Perna, Laura, Hatimy, Abubakar, Altadonna, Ginevra Chioccioli, Graves, Lee M., Herring, Laura E., Hickey, Anthony J., Thalassinos, Konstantinos, Chapple, J. Paul and Wolter, Justin M.
(2022)
Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization.
Cell Reports, 41
(5)
, 111580.
ISSN 2211-1247
[Article]
(doi:10.1016/j.celrep.2022.111580)
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Abstract
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset cerebellar ataxia caused by mutations in SACS, which encodes the protein sacsin. Cellular ARSACS phenotypes include mitochondrial dysfunction, intermediate filament disorganization, and progressive death of cerebellar Purkinje neurons. It is unclear why the loss of sacsin causes these deficits or why they manifest as cerebellar ataxia. Here, we perform multi-omic profiling in sacsin knockout (KO) cells and identify alterations in microtubule dynamics and mislocalization of focal adhesion (FA) proteins, including multiple integrins. Deficits in FA structure, signaling, and function can be rescued by targeting PTEN, a negative regulator of FA signaling. ARSACS mice possess mislocalization of ITGA1 in Purkinje neurons and synaptic disorganization in the deep cerebellar nucleus (DCN). The sacsin interactome reveals that sacsin regulates interactions between cytoskeletal and synaptic adhesion proteins. Our findings suggest that disrupted trafficking of synaptic adhesion proteins is a causal molecular deficit in ARSACS.
| Item Type: | Article |
|---|---|
| Sustainable Development Goals: | |
| Theme: | |
| Keywords (uncontrolled): | Integrins - genetics, microtubules, Mutation, CP: Neuroscience, Animals, Ataxia - genetics, synaptic adhesion proteins, focal adhesions, ARSACS, integrins, sacsin, Cerebellar Ataxia, Heat-Shock Proteins - metabolism, cell surface, synapse, proteomics, Purkinje neurons, Mice |
| Research Areas: | A. > School of Science and Technology > Natural Sciences |
| Item ID: | 36793 |
| Notes on copyright: | Cell Reports 41, 111580, November 1, 2022
Crown Copyright © 2022 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Depositing User: | Jisc Publications Router |
| Date Deposited: | 21 Nov 2022 12:59 |
| Last Modified: | 21 Nov 2022 12:59 |
| URI: | https://eprints.mdx.ac.uk/id/eprint/36793 |
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