Selective vulnerability of tripartite synapses in amyotrophic lateral sclerosis

Matthew J. Broadhead, Calum Bonthron, Julia Waddington, William V. Smith, Maite F. Lopez, Sarah Burley, Jessica Valli, Fei Zhu, Noboru H. Komiyama, Colin Smith, Seth G. N. Grant, Gareth B. Miles*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Pages (from-to)471-486
Number of pages16
JournalActa Neuropathologica
Volume143
Issue number4
Early online date19 Mar 2022
DOIs
Publication statusPublished - Apr 2022

Keywords

  • ALS/MND
  • Astrocyte
  • Neurodegeneration
  • Synapse

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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