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 logoORCID:, 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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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:
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 (
Depositing User: Jisc Publications Router
Date Deposited: 21 Nov 2022 12:59
Last Modified: 21 Nov 2022 12:59

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