eprintid: 10129734 rev_number: 22 eprint_status: archive userid: 608 dir: disk0/10/12/97/34 datestamp: 2021-06-17 11:52:25 lastmod: 2021-12-06 23:32:56 status_changed: 2021-06-17 11:52:25 type: article metadata_visibility: show creators_name: Mejia Maza, A creators_name: Jarvis, S creators_name: Lee, WC creators_name: Cunningham, TJ creators_name: Schiavo, G creators_name: Secrier, M creators_name: Fratta, P creators_name: Sleigh, JN creators_name: Fisher, EMC creators_name: Sudre, CH title: NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F85 divisions: C08 divisions: D09 divisions: F99 divisions: D14 divisions: GA3 divisions: G17 keywords: Amyotrophic lateral sclerosis, Diseases of the nervous system, Neuromuscular junction, Peripheral nervous system note: 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:// creat iveco mmons. org/ licen ses/ by/4. 0/. abstract: The neuromuscular junction (NMJ) is the peripheral synapse formed between a motor neuron axon terminal and a muscle fibre. NMJs are thought to be the primary site of peripheral pathology in many neuromuscular diseases, but innervation/denervation status is often assessed qualitatively with poor systematic criteria across studies, and separately from 3D morphological structure. Here, we describe the development of 'NMJ-Analyser', to comprehensively screen the morphology of NMJs and their corresponding innervation status automatically. NMJ-Analyser generates 29 biologically relevant features to quantitatively define healthy and aberrant neuromuscular synapses and applies machine learning to diagnose NMJ degeneration. We validated this framework in longitudinal analyses of wildtype mice, as well as in four different neuromuscular disease models: three for amyotrophic lateral sclerosis (ALS) and one for peripheral neuropathy. We showed that structural changes at the NMJ initially occur in the nerve terminal of mutant TDP43 and FUS ALS models. Using a machine learning algorithm, healthy and aberrant neuromuscular synapses are identified with 95% accuracy, with 88% sensitivity and 97% specificity. Our results validate NMJ-Analyser as a robust platform for systematic and structural screening of NMJs, and pave the way for transferrable, and cross-comparison and high-throughput studies in neuromuscular diseases. date: 2021-06-10 date_type: published official_url: https://doi.org/10.1038/s41598-021-91094-6 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1870809 doi: 10.1038/s41598-021-91094-6 pii: 10.1038/s41598-021-91094-6 lyricists_name: Fisher, Elizabeth lyricists_name: Fratta, Pietro lyricists_name: Lee, Weaverly Colleen Co lyricists_name: Schiavo, Giampietro lyricists_name: Secrier, Maria lyricists_name: Sleigh, James lyricists_name: Sudre, Carole lyricists_id: EMCFI97 lyricists_id: PFRAT57 lyricists_id: WCCLE97 lyricists_id: GSCHI71 lyricists_id: MSECR66 lyricists_id: JSLEI96 lyricists_id: SUDRE45 actors_name: Barczynska, Patrycja actors_id: PBARC91 actors_role: owner full_text_status: public publication: Scientific Reports volume: 11 number: 1 article_number: 12251 event_location: England citation: Mejia Maza, A; Jarvis, S; Lee, WC; Cunningham, TJ; Schiavo, G; Secrier, M; Fratta, P; ... Sudre, CH; + view all <#> Mejia Maza, A; Jarvis, S; Lee, WC; Cunningham, TJ; Schiavo, G; Secrier, M; Fratta, P; Sleigh, JN; Fisher, EMC; Sudre, CH; - view fewer <#> (2021) NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease. Scientific Reports , 11 (1) , Article 12251. 10.1038/s41598-021-91094-6 <https://doi.org/10.1038/s41598-021-91094-6>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10129734/1/Schiavo_s41598-021-91094-6.pdf