Myelin is a multi-lamellar structure that surrounds axons in both the CNS and PNS facilitating nerve conduction. MPZ,a transmembrane glycoprotein of the immunoglobulin supergene family, is the major structural protein in PNS myelin, and is expressed exclusively in Schwann cells, the myelinating glia. Human mutations in MPZ give rise to peripheral demyelinating neuropathies, Charcot Marie Tooth disease type IB (CMT1B). Several lines of evidence demonstrate that MPZ acts as a homophilic adhesion moleculeand, through its cytoplasmic domain, participates in a signal transduction cascade. Both the extracellular and intracellular domains of MPZ are necessary for homophilic adhesion in vitro and for myelination in vivo, hi order to more fully explore the molecular mechanisms by which mutations in MPZ cause neuropathy, we evaluated the clinical phenotype of 77 patients with CMT1B and correlated this to their genotype. We found that these patients fell into two distinct groups: one with disease onset in infancy, extremely slow nerve conductions, and pathological evidence of dysmyelination;and a second with disease onset as adults, essentially normal nerve conductions, and pathological evidence of axonal loss. Importantly, loss of MPZ adhesion did not correlate with either disease severity or the age of disease onset. These data suggest, however, that there are at least two separate disease mechanisms in CMT1B: one that effects myelin development, causing early onset disease, and a second that alters myelin maintenance, causing late onset disease. To further investigate the mechanisms of neuropathy in CMT1B we have produced three mouse models of the disease by homologous recombination and have also analyzed the expression of these mutant forms of MPZ in vitro and in human pathological material. Preliminary analysis of a mouse line carrying a Q186X mutation, causing early onset disease, suggests that this truncated protein acts like a dominant negative inhibitor of MPZ adhesion, consistent with the lack of compaction in nerve biopsies from patients with this mutation. In vitro analysis of a second mutation, R69C, for which we also have a mouse model, demonstrates that this protein does not reach the cell surface, suggesting that it causes disease by a """"""""gain of function"""""""" mechanism. Evaluation of nerves from a patient with the R69C mutation further suggests that the mutation effects myelin development. Finally, analysis of the nerve pathology and in vitro expression of two mutations, HI OPand T95M, causing late onset neuropathy suggest that these mutant proteins are incorporated into myelin where they produces a """"""""dying back gliopathy"""""""" by altering the process of myelin maintenance, and we have produced a mouse line encoding the T95M mutation, hi this grant we will analyze further the consequences of these MPZ mutations in the peripheral nerves of our mouse models, in transfected cells, and in human pathological material.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041319-09
Application #
7750496
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Gwinn, Katrina
Project Start
2001-04-05
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
9
Fiscal Year
2010
Total Cost
$325,516
Indirect Cost
Name
Wayne State University
Department
Neurology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Saporta, Mario A; Shy, Michael E (2013) Inherited peripheral neuropathies. Neurol Clin 31:597-619
Patzkó, Agnes; Bai, Yunhong; Saporta, Mario A et al. (2012) Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice. Brain 135:3551-66
Prada, Valeria; Passalacqua, Mario; Bono, Maria et al. (2012) Gain of glycosylation: a new pathomechanism of myelin protein zero mutations. Ann Neurol 71:427-31
Miller, Lindsey J; Patzko, Agnes; Lewis, Richard A et al. (2012) Phenotypic presentation of the Ser63Del MPZ mutation. J Peripher Nerv Syst 17:197-200
Saporta, Mario A C; Shy, Brian R; Patzko, Agnes et al. (2012) MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B. Brain 135:2032-47
Patzkó, Agnes; Shy, Michael E (2011) Update on Charcot-Marie-Tooth disease. Curr Neurol Neurosci Rep 11:78-88
Shy, Michael E; Patzko, Agnes (2011) Axonal Charcot-Marie-Tooth disease. Curr Opin Neurol 24:475-83
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Grandis, Marina; Vigo, Tiziana; Passalacqua, Mario et al. (2008) Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations. Hum Mol Genet 17:1877-89
Jani-Acsadi, Agnes; Krajewski, Karen; Shy, Michael E (2008) Charcot-Marie-Tooth neuropathies: diagnosis and management. Semin Neurol 28:185-94

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