title: P2X7-mediated increased intracellular calcium causes functional derangement in Schwann cells from rats with CMT1A neuropathy.
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.
authors: Department of Neurosciences, Ophthalmology, and Genetics and Center of Excellence for Biomedical Research, University of Genova, Via De Toni 5, 16132 Genova, Italy.
authors: Lucilla
authors: L
authors: Nobbio
authors: Laura
authors: L
authors: Sturla
authors: Fulvia
authors: F
authors: Fiorese
authors: Cesare
authors: C
authors: Usai
authors: Giovanna
authors: G
authors: Basile
authors: Iliana
authors: I
authors: Moreschi
authors: Federica
authors: F
authors: Benvenuto
authors: Elena
authors: E
authors: Zocchi
authors: Antonio
authors: A
authors: De Flora
authors: Angelo
authors: A
authors: Schenone
authors: Santina
authors: S
authors: Bruzzone
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism* / Q000473:pathology; D003711:Demyelinating Diseases / Q000235:genetics / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D053078:Membrane Potential, Mitochondrial; D008853:Microscopy; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D058919:Purinergic P2 Receptor Antagonists; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D009185:Myelin Proteins; C546470:P2rx7 protein, rat; C489546:Pmp22 protein, rat; D058919:Purinergic P2 Receptor Antagonists; D034741:RNA, Small Interfering; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002118:Calcium