Impaired expression of ciliary neurotrophic factor in Charcot-Marie-Tooth type 1A neuropathy.
We investigated the contribution of Schwann cell-derived ciliary neurotrophic factor (CNTF) to the pathogenesis of Charcot-Marie-Tooth disease type 1A (CMT1A) and addressed the question as to whether it plays a role in the development of axonal damage observed in the disease, with aging. Ciliary neurotrophic factor was underexpressed in experimental CMT1A but not in other models of hereditary neuropathies. Sciatic nerve crush experiments and dosage of CNTF at different time points showed that expression of this trophic factor remained significantly lower in CMT1A rats than in normal controls; moreover, in uninjured CMT1A sciatic nerves CNTF levels further decreased with ageing, thus paralleling the molecular signs of axonal impairment, that is increased expression of non-phosphorylated neurofilaments and amyloid precursor protein. Administration of CNTF to dorsal root ganglia cultures reduced dephosphorylation of neurofilaments in CMT1A cultures, without improving demyelination. Taken together, these results provide further evidence that the production of CNTF by Schwann cells is markedly reduced in CMT1A. Moreover, the observations suggest that trophic support to the axon is impaired in CMT1A and that further studies on the therapeutic use of trophic factors or their derivatives in experimental and human CMT1A are warranted.
Nobbio
Lucilla
L
Department of Neurosciences, Ophthalmology and Genetics, Center of Excellence for Biomedical Research, University of Genoa, Italy. Inobbio@neurologia.unige.it
Fiorese
Fulvia
F
Vigo
Tiziana
T
Cilli
Michele
M
Gherardi
Gianfranco
G
Grandis
Marina
M
Melcangi
Roberto Cosimo
RC
Mancardi
Gianluigi
G
Abbruzzese
Michele
M
Schenone
Angelo
A
D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000473:pathology; D001706:Biopsy; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005727:Ganglia, Spinal / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009185:Myelin Proteins / Q000235:genetics*; D016900:Neurofilament Proteins; D051381:Rats; D055647:Rats, Transgenic; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D012584:Sciatic Nerve / Q000166:cytology; D020426:Sciatic Neuropathy / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D020934:Ciliary Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D009185:Myelin Proteins; D016900:Neurofilament Proteins; C489546:Pmp22 protein, rat; D050796:STAT3 Transcription Factor