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
Type | Article |
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Title | Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization |
Authors | 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. |
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. |
Keywords | 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 |
Sustainable Development Goals | 3 Good health and well-being |
Middlesex University Theme | Health & Wellbeing |
Publisher | Cell Press |
Journal | Cell Reports |
ISSN | 2211-1247 |
Publication dates | |
Online | 01 Nov 2022 |
01 Nov 2022 | |
Publication process dates | |
Deposited | 21 Nov 2022 |
Submitted | 04 Oct 2021 |
Accepted | 07 Oct 2022 |
Output status | Published |
Publisher's version | License |
Copyright Statement | Cell Reports 41, 111580, November 1, 2022 |
Digital Object Identifier (DOI) | https://doi.org/10.1016/j.celrep.2022.111580 |
Language | English |
https://repository.mdx.ac.uk/item/8q283
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