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Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization

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 cereb...

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Autores principales: Romano, Lisa E.L., Aw, Wen Yih, Hixson, Kathryn M., Novoselova, Tatiana V., 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, Wolter, Justin M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9647044/
https://www.ncbi.nlm.nih.gov/pubmed/36323248
http://dx.doi.org/10.1016/j.celrep.2022.111580
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author Romano, Lisa E.L.
Aw, Wen Yih
Hixson, Kathryn M.
Novoselova, Tatiana V.
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
Wolter, Justin M.
author_facet Romano, Lisa E.L.
Aw, Wen Yih
Hixson, Kathryn M.
Novoselova, Tatiana V.
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
Wolter, Justin M.
author_sort Romano, Lisa E.L.
collection PubMed
description 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.
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spelling pubmed-96470442022-11-14 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 V. 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 Wolter, Justin M. Cell Rep Article 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. Cell Press 2022-11-01 /pmc/articles/PMC9647044/ /pubmed/36323248 http://dx.doi.org/10.1016/j.celrep.2022.111580 Text en Crown Copyright © 2022. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Romano, Lisa E.L.
Aw, Wen Yih
Hixson, Kathryn M.
Novoselova, Tatiana V.
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
Wolter, Justin M.
Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization
title Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization
title_full Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization
title_fullStr Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization
title_full_unstemmed Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization
title_short Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization
title_sort multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9647044/
https://www.ncbi.nlm.nih.gov/pubmed/36323248
http://dx.doi.org/10.1016/j.celrep.2022.111580
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