QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, February 22, 2006, 26(8):2358-2368; doi:10.1523/JNEUROSCI.3819-05.2006

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Wrabetz, L. Articles by Quattrini, A. Search for Related Content PubMed PubMed Citation Articles by Wrabetz, L. Articles by Quattrini, A.

 Previous Article

Neurobiology of Disease
Different Intracellular Pathomechanisms Produce Diverse Myelin Protein Zero Neuropathies in Transgenic Mice

Lawrence Wrabetz,^1 * Maurizio D’Antonio,^1 * Maria Pennuto,¹ Gabriele Dati,¹ Elisa Tinelli,¹ Pietro Fratta,¹ Stefano Previtali,² Daniele Imperiale,¹ Jurgen Zielasek,³ Klaus Toyka,³ Robin L. Avila,⁴ Daniel A. Kirschner,⁴ Albee Messing,⁵ M. Laura Feltri,¹ and Angelo Quattrini²

¹DIBIT and ²Department of Neurology, San Raffaele Scientific Institute, 20132 Milano, Italy, ³Department of Neurology, University of Würzburg, D97080 Würzburg, Germany, ⁴Biology Department, Boston College, Chestnut Hill, Massachusetts 02467, and ⁵Waisman Center and Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706

Correspondence should be addressed to Lawrence Wrabetz, San Raffaele Scientific Institute, DIBIT, Via Olgettina 58, 20132 Milan, Italy. Email: l.wrabetz{at}hsr.it

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 [Déjérine-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.

Key words: Charcot–Marie–Tooth neuropathy; myelin protein zero; packing; Schwann cell; traffic; transgene

---

Received Sept. 9, 2005; revised Jan. 17, 2006; accepted Jan. 17, 2006.

Correspondence should be addressed to Lawrence Wrabetz, San Raffaele Scientific Institute, DIBIT, Via Olgettina 58, 20132 Milan, Italy. Email: l.wrabetz{at}hsr.it

This article has been cited by other articles:

				M. Grandis, T. Vigo, M. Passalacqua, M. Jain, S. Scazzola, V. La Padula, M. Brucal, F. Benvenuto, L. Nobbio, A. Cadoni, et al. Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations Hum. Mol. Genet., July 1, 2008; 17(13): 1877 - 1889. [Abstract] [Full Text] [PDF]

				M. E. Shy, C. Siskind, E. R. Swan, K. M. Krajewski, T. Doherty, D. R. Fuerst, P. J. Ainsworth, R. A. Lewis, S. S. Scherer, and A. F. Hahn CMT1X phenotypes represent loss of GJB1 gene function Neurology, March 13, 2007; 68(11): 849 - 855. [Abstract] [Full Text] [PDF]

				V. Timmerman and D. N. Herrmann A "nerve" ending story in the identification of mutations in Charcot-Marie-Tooth neuropathy. Neurology, October 10, 2006; 67(7): 1114 - 1115. [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help