CMT 1A: Myelin Protein PMP22 in a transgenic rat model of Charcot Marie Tooth

[Guest guest]

Myelin Protein PMP22 in a transgenic rat model of Charcot-Marie-Tooth

Disease (CMT1A)

http://www.em.mpg.de/index.php?id=120 & L=1 & tx_jppageteaser_pi1%

5BbackId%5D=16 (photos at link)

W. Sereda, Gerd Meyer zu Hörste, Naureen Uzma, Prukop

(In collaboration with Ueli Suter, Zurich)

Tetraspan myelin proteins play an important role in CNS and PNS

myelination. We have generated a transgenic rat model of the most

frequent human neuropathy, Charcot-Marie-Tooth disease type 1A

(CMT1A). This disease is associated with a partial duplication of

chromosome 17 and we have proven experimentally that the underlying

cause is overexpression of the PMP22 gene.

Transgenic rats expressing additional copies of this gene share

characteristic clinical features of the human disease, including

muscle weakness, reduced nerve conduction velocities, and marked

Schwann cell hypertrophy resulting in onion bulb formation.

Typical onion-bulb formation of a 6 month-old CMT-rat showing

concentric layers of Schwann cell processes and redundant basal

laminae around a naked axon.

PMP22 overexpression may result in defects of intracellular protein

trafficking. The rat model allows to adress the molecular pathology

of CMT1A in more detail than previously possible with human biopsy

material. We are specifically interested in the ultrastructural

analysis of presymptomatic Schwann cells at early disease stages.

Moreover, we are applying the tools of biochemistry and radioactive

labeling of protein synthesis (ex vivo) to study the kinetics of

myelination and intracellular protein sorting.

When bred to homozygosity, PMP22 transgenic rats completely fail to

elaborate myelin and Schwann cells appear to be developmentally

arrested at the " promyelin " stage. However, all myelin genes which

mark the mature Schwann cell phenotype are normally expressed. Thus,

a several-fold PMP22 overexpression causes a novel uncoupling of the

molecular and morphological parameters of Schwann cell

differentiation.

Steroid hormones have recently been identified as coregulators of

Schwann cell function and peripheral myelination. Progesterone

increases the expression of PMP22 in Schwann cell cultures and in the

peripheral nervous system in vivo.

In an attempt to lower PMP22 overexpression, we applied the

progesterone receptor antagonist Onapristone to CMT-rats. Daily

administration of progesterone elevated the steady-state levels of

Pmp22 and Mpz mRNA in the sciatic nerve, resulting in enhanced

Schwann cell pathology and a more progressive clinical neuropathy.

In contrast, administration of the selective progesterone receptor

antagonist reduced overexpression of Pmp22 and improved the CMT

phenotype, without obvious side effects, in wild-type or transgenic

rats. Taken together, these data provide proof of principle that the

progesterone receptor of myelin-forming Schwann cells is a promising

pharmacological target for therapy of CMT-1A. We are currently

planning follow-up studies to pave the way to clinical application.

In summary, the CMT rat allows a better understanding of the cellular

disease mechanism operating in human CMT1A, and should be helpful in

the analysis of modifier genes, epigenetic factors, and in the

evaluation of experimental treatment strategies.