Weaverly Colleen Lee

All Publications

• NMJ-Analyser identifies subtle early changes in mouse models of neuromuscular disease SCIENTIFIC REPORTS Maza, A., Jarvis, S., Lee, W., Cunningham, T. J., Schiavo, G., Secrier, M., Fratta, P., Sleigh, J. N., Fisher, E. C., Sudre, C. H. 2021; 11 (1): 12251

  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.

  View details for DOI 10.1038/s41598-021-91094-6

  View details for Web of Science ID 000663785600001

  View details for PubMedID 34112844

  View details for PubMedCentralID PMC8192785

• A novel knockout mouse for the small EDRK-rich factor 2 (Serf2) showing developmental and other deficits MAMMALIAN GENOME Cleverley, K., Lee, W., Mumford, P., Collins, T., Rickman, M., Cunningham, T. J., Cleak, J., Mianne, J., Szoke-Kovacs, Z., Stewart, M., Teboul, L., Maduro, C., Wells, S., Wiseman, F. K., Fisher, E. C. 2021; 32 (2): 94-103

  Abstract

  The small EDRK-rich factor 2 (SERF2) is a highly conserved protein that modifies amyloid fibre assembly in vitro and promotes protein misfolding. However, the role of SERF2 in regulating age-related proteotoxicity remains largely unexplored due to a lack of in vivo models. Here, we report the generation of Serf2 knockout mice using an ES cell targeting approach, with Serf2 knockout alleles being bred onto different defined genetic backgrounds. We highlight phenotyping data from heterozygous Serf2+/- mice, including unexpected male-specific phenotypes in startle response and pre-pulse inhibition. We report embryonic lethality in Serf2-/- null animals when bred onto a C57BL/6 N background. However, homozygous null animals were viable on a mixed genetic background and, remarkably, developed without obvious abnormalities. The Serf2 knockout mice provide a powerful tool to further investigate the role of SERF2 protein in previously unexplored pathophysiological pathways in the context of a whole organism.

  View details for DOI 10.1007/s00335-021-09864-6

  View details for Web of Science ID 000628461600001

  View details for PubMedID 33713180

  View details for PubMedCentralID PMC8012326