NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease
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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-06-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-91094-6 |
| _version_ | 1818435105525334016 |
|---|---|
| author | Alan Mejia Maza Seth Jarvis Weaverly Colleen Lee Thomas J. Cunningham Giampietro Schiavo Maria Secrier Pietro Fratta James N. Sleigh Elizabeth M. C. Fisher Carole H. Sudre |
| author_facet | Alan Mejia Maza Seth Jarvis Weaverly Colleen Lee Thomas J. Cunningham Giampietro Schiavo Maria Secrier Pietro Fratta James N. Sleigh Elizabeth M. C. Fisher Carole H. Sudre |
| author_sort | Alan Mejia Maza |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T16:47:36Z |
| format | Article |
| id | doaj.art-3ff0e26ea9ca4cddb08257a5dd74ce5e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T16:47:36Z |
| publishDate | 2021-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-3ff0e26ea9ca4cddb08257a5dd74ce5e2022-12-21T22:54:08ZengNature PortfolioScientific Reports2045-23222021-06-0111111710.1038/s41598-021-91094-6NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular diseaseAlan Mejia Maza0Seth Jarvis1Weaverly Colleen Lee2Thomas J. Cunningham3Giampietro Schiavo4Maria Secrier5Pietro Fratta6James N. Sleigh7Elizabeth M. C. Fisher8Carole H. Sudre9Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College LondonDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College LondonDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College LondonMammalian Genetics Unit, MRC Harwell InstituteDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College LondonDepartment of Genetics, Evolution and Environment, UCL Genetic Institute, University College LondonDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College LondonDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College LondonDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College LondonMRC Unit for Lifelong Health and Ageing, Department of Population Science and Experimental Medicine, University College LondonAbstract 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.https://doi.org/10.1038/s41598-021-91094-6 |
| spellingShingle | Alan Mejia Maza Seth Jarvis Weaverly Colleen Lee Thomas J. Cunningham Giampietro Schiavo Maria Secrier Pietro Fratta James N. Sleigh Elizabeth M. C. Fisher Carole H. Sudre NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease Scientific Reports |
| title | NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease |
| title_full | NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease |
| title_fullStr | NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease |
| title_full_unstemmed | NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease |
| title_short | NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease |
| title_sort | nmj analyser identifies subtle early changes in mouse models of neuromuscular disease |
| url | https://doi.org/10.1038/s41598-021-91094-6 |
| work_keys_str_mv | AT alanmejiamaza nmjanalyseridentifiessubtleearlychangesinmousemodelsofneuromusculardisease AT sethjarvis nmjanalyseridentifiessubtleearlychangesinmousemodelsofneuromusculardisease AT weaverlycolleenlee nmjanalyseridentifiessubtleearlychangesinmousemodelsofneuromusculardisease AT thomasjcunningham nmjanalyseridentifiessubtleearlychangesinmousemodelsofneuromusculardisease AT giampietroschiavo nmjanalyseridentifiessubtleearlychangesinmousemodelsofneuromusculardisease AT mariasecrier nmjanalyseridentifiessubtleearlychangesinmousemodelsofneuromusculardisease AT pietrofratta nmjanalyseridentifiessubtleearlychangesinmousemodelsofneuromusculardisease AT jamesnsleigh nmjanalyseridentifiessubtleearlychangesinmousemodelsofneuromusculardisease AT elizabethmcfisher nmjanalyseridentifiessubtleearlychangesinmousemodelsofneuromusculardisease AT carolehsudre nmjanalyseridentifiessubtleearlychangesinmousemodelsofneuromusculardisease |