CMT 1A: Impaired Expression of Ciliary Neurotrophic Factor

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J Neuropathol Exp Neurol. 2009 May;68(5):441-455.

Impaired Expression of Ciliary Neurotrophic Factor in Charcot-Marie-Tooth Type

1A Neuropathy.

Nobbio L, Fiorese F, Vigo T, Cilli M, Gherardi G, Grandis M, Melcangi RC,

Mancardi G, Abbruzzese M, Schenone A.

From the Department of Neurosciences, Ophthalmology and Genetics (LN, FF, TV,

GG, MG, GM, MA, AS); Center of Excellence for Biomedical Research (LN, FF, GM,

AS), University of Genoa; Animal Facility Unit (MC), National Cancer Research

Institute, Genoa, Italy; and Department of Endocrinology and Center of

Excellence on Neurodegenerative Diseases (RCM), University of Milan, Milan,

Italy.

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.