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Selective vulnerability of tripartite synapses in Amyotrophic Lateral Sclerosis

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Date
04/2022
Author
Broadhead, Matthew J.
Bonthron, Calum
Waddington, Julia
Smith, William V.
Lopez, Maite F.
Burley, Sarah
Valli, Jessica
Zhu, Fei
Komiyama, Noboru H.
Smith, Colin
Grant, Seth G.N.
Miles, Gareth B.
Funder
Chief Scientist Office
Motor Neurone Disease Association
Grant ID
3752534
137/813
Keywords
ALS/MND
Synapse
Astrocyte
Neurodegeneration
RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
NDAS
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Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Separate lines of evidence suggest that synapses and astrocytes play a role in the pathological mechanisms underlying ALS. Given that astrocytes make specialised contacts with some synapses, called tripartite synapses, we hypothesise that tripartite synapses could act as the fulcrum of disease in ALS. To test this hypothesis, we have performed an extensive microscopy-based investigation of synapses and tripartite synapses in the spinal cord of ALS model mice and post-mortem human tissue from ALS cases. We reveal widescale synaptic changes at the early symptomatic stages of the SOD1G93a mouse model. Super-resolution microscopy reveals that large complex postsynaptic structures are lost in ALS mice. Most surprisingly, tripartite synapses are selectively lost, while non-tripartite synapses remain in equal number to healthy controls. Finally, we also observe a similar selective loss of tripartite synapses in human post-mortem ALS spinal cords. From these data we conclude that tripartite synaptopathy is a key hallmark of ALS.
Citation
Broadhead , M J , Bonthron , C , Waddington , J , Smith , W V , Lopez , M F , Burley , S , Valli , J , Zhu , F , Komiyama , N H , Smith , C , Grant , S G N & Miles , G B 2022 , ' Selective vulnerability of tripartite synapses in Amyotrophic Lateral Sclerosis ' , Acta Neuropathologica , vol. 143 , no. 4 , pp. 471–486 . https://doi.org/10.1007/s00401-022-02412-9
Publication
Acta Neuropathologica
Status
Peer reviewed
DOI
https://doi.org/10.1007/s00401-022-02412-9
ISSN
0001-6322
Type
Journal article
Rights
Copyright © The Author(s) 2022. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Description
Authors would like to acknowledge the following funders: Motor Neurone Disease (MND) Association UK (Miles/Apr18/863-791), the Euan MacDonald Centre and Chief Scientist Office, The European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (695568 SYNNOVATE), Simons Foundation Autism Research Initiative (529085), and the Wellcome Trust (Technology Development grant 202932).
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/25081

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