Characterization of the NeflE396K mouse model for Charcot-Marie-Tooth type 2E (CMT2E) therapeutic development


Pre-Clinical Research

Poster Number: T400


Dennis Perez-Lopez, BS, University of Missouri-Columbia, Audrey A. Shively, University of Missouri, Mohammed T. Abu-Salah, University of Missouri, Sara M. Ricardez Hernandez, BS, University of Missouri, Mona O. Kacher, University of Missouri, F. Javier Llorente Torres, MS, University of Missouri, W. David Arnold, MD, Department of Physical Medicine and Rehabilitation, University of Missouri School of Medicine, Colum, Monique A. Lorson, PhD, University of Missouri, Christian L. Lorson, PhD, University of Missouri

CMT is the most common hereditary peripheral neuropathy with an incidence of 1:2,500. CMT2 is a type of CMT that presents as a slow, progressive disorder associated with axonal dysfunction. CMT2 clinical symptoms include distal muscle weakness and atrophy, sensory loss, toe and foot deformities, and reduced nerve conduction velocity. CMT2E is a type of CMT2 associated with mutations in the gene neurofilament light chain (NEFL). The protein, NF-L, is one of five subunits that makes up neurofilaments and contributes to the axonal cytoskeleton. CMT2E is typically inherited in an autosomal dominant manner with variable onset and severity. To advance the development of therapeutics for Charcot-Marie-Tooth (CMT) type 2E (CMT2E) and to better understand the underlying biology of disease progression, we generated Nefl+/E396K and NeflE396K/E396K mice. Motor function, balance, and strength assessments were performed on the Nefl mice to evaluate disease progression. Additionally, muscle pathology, innervation status, nerve morphology, and in vivo measurements of neuronal function have been performed. Our new mouse models, Nefl+/E396K and NeflE396K/E396K, present axonal defects at P21 and showed a reduced compound muscle action potential (CMAP), reduced negative area, and increased distal latency. At 6 months and 12 moths months disease progression is more evident in terms of distal latency and showed a more significant functional deficit. Muscle atrophy and denervation is present at 3 weeks of age. Cross-sectional images of the sciatic nerve showed axonal degeneration and myelination defects in Nefl+/E396K and NeflE396K/E396K mice starting at 3 weeks. Collectively, our thorough phenotyping of these novel mouse models of disease conclusively demonstrates that there is an early and quantifiable neurological phenotype in our novel CMT2E mice, making it ideal for the evaluation of therapeutic approaches.