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

Article

Romano, L., Aw, W., Hixson, K., Novoselova, T., Havener, T., Howell, S., Taylor-Blake, B., Hall, C., Xing, L., Beri, J., Nethisinghe, S., Perna, L., Hatimy, A., Altadonna, G., Graves, L., Herring, L., Hickey, A., Thalassinos, K., Chapple, J. and Wolter, J. 2022. Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization. Cell Reports. 41 (5). https://doi.org/10.1016/j.celrep.2022.111580
TypeArticle
TitleMulti-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization
AuthorsRomano, L., Aw, W., Hixson, K., Novoselova, T., Havener, T., Howell, S., Taylor-Blake, B., Hall, C., Xing, L., Beri, J., Nethisinghe, S., Perna, L., Hatimy, A., Altadonna, G., Graves, L., Herring, L., Hickey, A., Thalassinos, K., Chapple, J. and Wolter, J.
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.

KeywordsIntegrins - 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
Sustainable Development Goals3 Good health and well-being
Middlesex University ThemeHealth & Wellbeing
PublisherCell Press
JournalCell Reports
ISSN2211-1247
Publication dates
Online01 Nov 2022
Print01 Nov 2022
Publication process dates
Deposited21 Nov 2022
Submitted04 Oct 2021
Accepted07 Oct 2022
Output statusPublished
Publisher's version
License
Copyright Statement

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/).

Digital Object Identifier (DOI)https://doi.org/10.1016/j.celrep.2022.111580
LanguageEnglish
Permalink -

https://repository.mdx.ac.uk/item/8q283

Log in to edit

Download files

Publisher's version
Romano_et.al-Multi-omicProfiling_mmc10.pdf
License: CC BY-NC-ND 4.0

  • 32
    total views
  • 20
    total downloads
  • 2
    views this month
  • 4
    downloads this month

Export as