Early abnormalities in sciatic nerve function and structure in a rat model of Charcot-Marie-Tooth type 1A disease.
We investigated early peripheral nervous system impairment in PMP22-transgenic rats ("CMT rat"), an established animal model for Charcot-Marie-Tooth disease 1A, at postnatal day 30 (P30), when the clinical phenotype is not yet apparent. Hemizygous CMT1A rats and wildtype littermates were studied by means of behavioral examination, electrophysiology, molecular biology, and light microscopy analysis. Behavioral studies only showed, a mild, but significant, decrease in toe spread 1-5, suggesting a weakness of distal foot muscles in CMT1A rats compared with normal littermates. Nerve conduction studies disclosed a severe slowing in motor conduction velocity, a temporal dispersion and a dramatic decrease of amplitude of motor waves in P30 transgenic animals. Coherently with a demyelinating process, affected nerves showed a significant thinning of myelin. Interestingly, axonal diameter and area were unchanged, but expression of non-phosphorylated neurofilaments was increased in CMT1A rats compared with normal controls. Our results confirm the fidelity of this animal model to human disease. Similarly, in young CMT1A patients, the MCV is significantly reduced and the muscle weakness is confined to distal segments, whereas morphological and morphometrical signs of axonal atrophy are absent. However, the presence of a molecular and functional damage of the axons suggests that this may be the correct moment to start neuroprotective therapies.
Grandis
Marina
M
Department of Neuroscience, Ophthalmology and Genetics, University of Genoa, Via de Toni 5, 16132 Genoa, Italy. mgrandis71@hotmail.com
Leandri
Massimo
M
Vigo
Tiziana
T
Cilli
Michele
M
Sereda
Michael W
MW
Gherardi
Gianfranco
G
Benedetti
Luana
L
Mancardi
Gianluigi
G
Abbruzzese
Michele
M
Nave
Klaus-Armin
KA
Nobbio
Lucilla
L
Schenone
Angelo
A
D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000473:pathology; D001522:Behavior, Animal; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004594:Electrophysiology; D020022:Genetic Predisposition to Disease; D051379:Mice; D009043:Motor Activity / Q000235:genetics; D018908:Muscle Weakness / Q000235:genetics / Q000503:physiopathology; D009185:Myelin Proteins / Q000235:genetics; D009186:Myelin Sheath / Q000473:pathology; D009431:Neural Conduction / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology; D020426:Sciatic Neuropathy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*
D009185:Myelin Proteins; C489545:Pmp22 protein, mouse; D012333:RNA, Messenger