Selective vulnerability of tripartite synapses in amyotrophic lateral sclerosis

• Published in: Acta neuropathologica Vol. 143; no. 4; pp. 471 - 486
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2022; Springer; Springer Nature B.V
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - pathology; Animal models; Animals; Astrocytes; Autopsy; Disease Models, Animal; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Microscopy; Motor Neurons - pathology; Nervous system diseases; Neurodegenerative diseases; Neurosciences; Original Paper; Pathology; Spinal cord; Spinal Cord - pathology; Superoxide Dismutase; Superoxide Dismutase-1 - genetics; Synapses; Synapses - pathology; ALS/MND; Synapse; Astrocyte; Neurodegeneration
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-022-02412-9

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 SOD1 G93a 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.