title: Muscle spindle alterations precede onset of sensorimotor deficits in Charcot-Marie-Tooth type 2E.
abstract: Charcot-Marie-Tooth (CMT) is the most common inherited peripheral neuropathy, affecting approximately 2.8 million people. The CMT leads to distal neuropathy that is characterized by reduced motor nerve conduction velocity, ataxia, muscle atrophy and sensory loss. We generated a mouse model of CMT type 2E (CMT2E) expressing human neurofilament light E396K (hNF-LE396K), which develops decreased motor nerve conduction velocity, ataxia and muscle atrophy by 4 months of age. Symptomatic hNF-LE396Kmice developed phenotypes that were consistent with proprioceptive sensory defects as well as reduced sensitivity to mechanical stimulation, while thermal sensitivity and auditory brainstem responses were unaltered. Progression from presymptomatic to symptomatic included a 50% loss of large diameter sensory axons within the fifth lumbar dorsal root of hNF-LE396Kmice. Owing to proprioceptive deficits and loss of large diameter sensory axons, we analyzed muscle spindle morphology in presymptomatic and symptomatic hNF-LE396Kand hNF-L control mice. Muscle spindle cross-sectional area and volume were reduced in all hNF-LE396Kmice analyzed, suggesting that alterations in muscle spindle morphology occurred prior to the onset of typical CMT pathology. These data suggested that CMT2E pathology initiated in the muscle spindles altering the proprioceptive sensory system. Early sensory pathology in CMT2E could provide a unifying hypothesis for the convergence of pathology observed in CMT.
authors.affiliation: Division of Biological Sciences, Columbia, MO, USA.|C. S. Bond Life Sciences Center, Columbia, MO, USA.
authors.forename: E
authors.initials: E
authors.lastname: Villalón
authors.affiliation: Division of Biological Sciences, Columbia, MO, USA.|C. S. Bond Life Sciences Center, Columbia, MO, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Jones
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri-Columbia, Columbia, MO, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sibigtroth
authors.affiliation: Division of Biological Sciences, Columbia, MO, USA.|C. S. Bond Life Sciences Center, Columbia, MO, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Zino
authors.affiliation: Division of Biological Sciences, Columbia, MO, USA.|C. S. Bond Life Sciences Center, Columbia, MO, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Dale
authors.affiliation: Quantitative and Systems Biology, University of California Merced, Merced, CA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Landayan
authors.affiliation: Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Shen
authors.affiliation: Division of Biological Sciences, Columbia, MO, USA.|C. S. Bond Life Sciences Center, Columbia, MO, USA.
authors.forename: D D W
authors.initials: DD
authors.lastname: Cornelison
authors.affiliation: Division of Biological Sciences, Columbia, MO, USA.|C. S. Bond Life Sciences Center, Columbia, MO, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Garcia
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009470:Muscle Spindles / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000235:genetics; D009154:Mutation; D009431:Neural Conduction / Q000502:physiology; D016900:Neurofilament Proteins / Q000235:genetics; D066191:Sensorimotor Cortex / Q000378:metabolism / Q000503:physiopathology
chemical_list: D016900:Neurofilament Proteins
keywords: Charcot-Marie-Tooth; muscle spindle; neurofilament; peripheral neuropathy; proprioception; sensory