Different intracellular pathomechanisms produce diverse Myelin Protein Zero neur

[Guest guest]

J Neurosci. 2006 Feb 22;26(8):2358-68.

Different intracellular pathomechanisms produce diverse Myelin

Protein Zero neuropathies in transgenic mice.

Wrabetz L, D' M, Pennuto M, Dati G, Tinelli E, Fratta P,

Previtali S, Imperiale D, Zielasek J, Toyka K, Avila RL, Kirschner

DA, Messing A, Feltri ML, Quattrini A.

DIBIT, San Raffaele Scientific Institute, 20132 Milan, Italy.

Missense mutations in 22 genes account for one-quarter of Charcot-

Marie-Tooth (CMT) hereditary neuropathies. Myelin Protein Zero (MPZ,

P0) mutations produce phenotypes ranging from adult demyelinating

(CMT1B) to early onset [Dejerine-Sottas syndrome (DSS) or congenital

hypomyelination] to predominantly axonal neuropathy, suggesting gain

of function mechanisms. To test this directly, we produced mice in

which either the MpzS63C (DSS) or MpzS63del (CMT1B) transgene was

inserted randomly, so that the endogenous Mpz alleles could

compensate for any loss of mutant P0 function. We show that either

mutant allele produces demyelinating neuropathy that mimics the

corresponding human disease. However, P0S63C creates a packing defect

in the myelin sheath, whereas P0S63del does not arrive to the myelin

sheath and is instead retained in the endoplasmic reticulum, where it

elicits an unfolded protein response (UPR). This is the first

evidence for UPR in association with neuropathy and provides a model

to determine whether and how mutant proteins can provoke

demyelination from outside of myelin.