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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Basile, Giovanna Zocchi, Elena Schenone, Angelo Nobbio, Lucilla Moreschi, Iliana Sturla, Laura Fiorese, Fulvia Bruzzone, Santina Benvenuto, Federica Usai, Cesare De Flora, Antonio |
| Description | Author Affiliation: Nobbio L ( Department of Neurosciences, Ophthalmology, and Genetics and Center of Excellence for Biomedical Research, University of Genova, Via De Toni 5, 16132 Genova, Italy.) |
| Abstract | Charcot-Marie-Tooth (CMT) is the most frequent inherited neuromuscular disorder, affecting 1 person in 2500. CMT1A, the most common form of CMT, is usually caused by a duplication of chromosome 17p11.2, containing the PMP22 (peripheral myelin protein-22) gene; overexpression of PMP22 in Schwann cells (SC) is believed to cause demyelination, although the underlying pathogenetic mechanisms remain unclear. Here we report an abnormally high basal concentration of intracellular calcium ([Ca(2+)](i)) in SC from CMT1A rats. By the use of specific pharmacological inhibitors and through down-regulation of expression by small interfering RNA, we demonstrate that the high [Ca(2+)](i) is caused by a PMP22-related overexpression of the P2X7 purinoceptor/channel leading to influx of extracellular Ca(2+) into CMT1A SC. Correction of the altered [Ca(2+)](i) in CMT1A SC by small interfering RNA or with pharmacological inhibitors of P2X7 restores functional parameters of SC (migration and release of ciliary neurotrophic factor), which are typically defective in CMT1A SC. More significantly, stable down-regulation of the expression of P2X7 restores myelination in co-cultures of CMT1A SC with dorsal root ganglion sensory neurons. These results establish a pathogenetic link between high [Ca(2+)](i) and impaired SC function in CMT1A and identify overexpression of P2X7 as the molecular mechanism underlying both abnormalities. The development of P2X7 inhibitors is expected to provide a new therapeutic strategy for treatment of CMT1A neuropathy. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 34 |
| Volume Number | 284 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2009-08-21 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Calcium Metabolism Charcot-Marie-Tooth Disease Receptors, Purinergic P2 Physiology Schwann Cells 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Analogs & Derivatives Pharmacology Animals Animals, Genetically Modified Blotting, Western Cells, Cultured Pathology Demyelinating Diseases Genetics Enzyme Inhibitors Gene Expression Regulation Drug Effects Immunohistochemistry Membrane Potential, Mitochondrial Microscopy Myelin Proteins Purinergic P2 Receptor Antagonists RNA, Small Interfering Rats, Sprague-Dawley Receptors, Purinergic P2X7 Reverse Transcriptase Polymerase Chain Reaction Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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