impaired axonal regeneration research

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Abstract from the Journal of the Peripheral Nervous System 2003

Jun;8(2):116-27.

(Note: Dr. Sahenk from OSU and who's been working on the first human

trials of NT-3 for CMT 1A, is a co-author of this collaborative

research)

Evidence for impaired axonal regeneration in PMP22 duplication: studies

in nerve xenografts.

Sahenk Z, Serrano-Munuera C, Chen L, Kakabadze I, Najagara HN.

Department of Neurology,1 Neuromuscular Disease Center, and Department

of Statistics, 3 The Ohio State University, Columbus, Ohio, USA;

Visiting fellow from Institut de Recerca, 2 Hospital Sta. Creu i St.

Pau, Barcelona, Spain.

Whether axonal regeneration in Charcot-Marie-Tooth (CMT) neuropathies is

impaired has not been addressed in detail. Our studies in nude mice

harboring xenografts from patients with different primary Schwann cell

(SC) genetic defects suggested an intimate association between the onset

of myelination and impairment in the growth capacity of nude mice axons

engulfed by the mutant SCs. To assess the effects of

peripheral myelin protein 22 (PMP22) gene duplication on the

regeneration process, we conducted morphometric studies to generate

temporal growth profiles of myelinated axons within the xenografts

obtained from CMT1A patients and from healthy controls.

Axon size distribution histograms in controls at different time

intervals revealed that size differentiation of myelinated fibers within

the grafts is established as

early as 2 weeks, and that the temporal pattern of myelination of

different sized axons has striking similarities to myelination during

development. In PMP22 duplication grafts, the onset of myelination is

delayed and the regeneration capacity of all fiber sizes is impaired.

This defect, however,is most pronounced for the large diameter axons. In

addition, significant large fiber loss occurred after 12 weeks with a

concomitant new cycle of regeneration of small size axons. These studies

show that

the PMP22 duplication in SCs have profound effects on the regeneration

process, which might be a contributing factor to preferential distal

axonal loss.