Animal models of inherited neuropathies

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Curr Opin Neurol. 2006 Oct;19(5):464-73.

Animal models of inherited neuropathies.

Zu Horste GM, Nave KA.

Max-Planck-Institute of Experimental Medicine, Gottingen, Germany.

PURPOSE OF REVIEW: Mutations in a number of genes have been

associated with inherited neuropathies (Charcot-Marie-Tooth or CMT

disease). This review highlights how animal models of demyelinating

CMT have improved our understanding of disease mechanisms. Transgenic

CMT models also allow therapies to be developed in a preclinical

setting.

RECENT FINDINGS: Rodent models for the most common subtypes of human

CMT disease are now available, and two mouse mutants modeling the

rare CMT4B subform have lately extended this repertoire. In a

peripheral myelin protein 22 kDa (Pmp22) transgenic rat model of

CMT1A, administration of a progesterone receptor antagonist

(onapristone) reduced Pmp22 overexpression, axon loss and clinical

impairments. Dietary ascorbic acid (Vitamin C) prevented

dysmyelination and premature death in a Pmp22 transgenic mouse line.

Neurotrophin-3 (NT-3) promoted small fiber remyelination in CMT1A

xenografts and sensory functions in CMT1A patients.

Gene expression profiling in rodent models of CMT may identify

further therapeutical targets. While original classifications

distinguish the demyelinating and axonal forms of CMT, recent

findings emphasize that axon loss is a common feature, possibly

caused by Schwann cell defects rather than demyelination per se. This

supports our model that myelination and long-term axonal support are

distinct functions of all myelinating glial cells.

SUMMARY: Animal models have opened up new perspectives on the

pathomechanisms and possible treatment strategies of inherited

neuropathies.