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The ataxia protein sacsin is required for integrin trafficking and synaptic organization

Lisa E.L. Romano, Wen Yih Aw, Kathryn M. Hixson, Tatiana V. Novoselova, Tammy M. Havener, Stefanie Howell, Charlotte L Hall, Lei Xing, Josh Beri, Suran Nethisinghe, Laura Perna, Abubakar Hatimy, Ginevra Chioccioli Altadonna, Lee M. Graves, Laura E. Herring, Anthony J. Hickey, Konstantinos Thalassinos, J. Paul Chapple, View ORCID ProfileJustin M. Wolter
doi: https://doi.org/10.1101/2021.08.20.456807
Lisa E.L. Romano
1William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
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Wen Yih Aw
2UNC Catalyst for Rare Diseases, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, U.S.A.
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Kathryn M. Hixson
2UNC Catalyst for Rare Diseases, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, U.S.A.
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Tatiana V. Novoselova
1William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
3Department of Natural Sciences, Faculty of Science and Technology, Middlesex University London, NW4 4BT United Kingdom
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Tammy M. Havener
2UNC Catalyst for Rare Diseases, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, U.S.A.
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Stefanie Howell
2UNC Catalyst for Rare Diseases, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, U.S.A.
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Charlotte L Hall
1William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
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Lei Xing
4UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, U.S.A.
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Josh Beri
5Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
6UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Suran Nethisinghe
1William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
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Laura Perna
1William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
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Abubakar Hatimy
7Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom
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Ginevra Chioccioli Altadonna
1William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
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Lee M. Graves
5Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
8Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Laura E. Herring
5Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
6UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Anthony J. Hickey
2UNC Catalyst for Rare Diseases, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, U.S.A.
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Konstantinos Thalassinos
7Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, WC1E 6BT, United Kingdom
9Institute of Structural and Molecular Biology, Birkbeck College, University of London, London, WC1E 7HX, United Kingdom
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J. Paul Chapple
1William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
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  • For correspondence: j.p.chapple@qmul.ac.uk justin_wolter@med.unc.edu
Justin M. Wolter
2UNC Catalyst for Rare Diseases, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, U.S.A.
4UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, U.S.A.
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  • ORCID record for Justin M. Wolter
  • For correspondence: j.p.chapple@qmul.ac.uk justin_wolter@med.unc.edu
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Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in SACS, which manifest as a childhood-onset cerebellar ataxia. Cellular ARSACS phenotypes include mitochondrial dysfunction, intermediate filament (IF) disorganization, and loss of Purkinje neurons. It is unclear how the loss of SACS causes these deficits, or why they manifest as cerebellar ataxia. We employed a multi-omics approach to characterize molecular and cellular deficiencies in SACS knockout (KO) cells. We identified alterations in microtubule structure and dynamics, protein trafficking, and mislocalization of synaptic and focal adhesion proteins. Targeting PTEN, a negative regulator of focal adhesions, rescued several cellular phenotypes in SACS KO cells. We found sacsin interacts with proteins implicated in vesicle transport, including HSP proteins, and interactions between structural and cell adhesion proteins were diminished in SACS KO cells. In all, this study suggests that trafficking and localization of synaptic adhesion proteins is a causal molecular deficiency in ARSACS.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 20, 2021.
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The ataxia protein sacsin is required for integrin trafficking and synaptic organization
Lisa E.L. Romano, Wen Yih Aw, Kathryn M. Hixson, Tatiana V. Novoselova, Tammy M. Havener, Stefanie Howell, Charlotte L Hall, Lei Xing, Josh Beri, Suran Nethisinghe, Laura Perna, Abubakar Hatimy, Ginevra Chioccioli Altadonna, Lee M. Graves, Laura E. Herring, Anthony J. Hickey, Konstantinos Thalassinos, J. Paul Chapple, Justin M. Wolter
bioRxiv 2021.08.20.456807; doi: https://doi.org/10.1101/2021.08.20.456807
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The ataxia protein sacsin is required for integrin trafficking and synaptic organization
Lisa E.L. Romano, Wen Yih Aw, Kathryn M. Hixson, Tatiana V. Novoselova, Tammy M. Havener, Stefanie Howell, Charlotte L Hall, Lei Xing, Josh Beri, Suran Nethisinghe, Laura Perna, Abubakar Hatimy, Ginevra Chioccioli Altadonna, Lee M. Graves, Laura E. Herring, Anthony J. Hickey, Konstantinos Thalassinos, J. Paul Chapple, Justin M. Wolter
bioRxiv 2021.08.20.456807; doi: https://doi.org/10.1101/2021.08.20.456807

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