Selective vulnerability of tripartite synapses in Amyotrophic Lateral Sclerosis
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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.
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
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DescriptionAuthors 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).
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