In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 26, No. 8 ( 2006-02-22), p. 2358-2368
Abstract:
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 Mpz S63C (DSS) or Mpz S63del (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.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.3819-05.2006
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2006
detail.hit.zdb_id:
1475274-8
SSG:
12
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