CMT 1A: P2X7 inhibitors is expected to provide a new therapeutic strategy

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J Biol Chem. 2009 Jun 22.

P2X7-mediated increased intracellular calcium causes functional derangement in

Schwann cells from rats with CMT1A neuropathy.

Nobbio L, Sturla L, Fiorese F, Usai C, Basile G, Moreschi I, Benvenuto F, Zocchi

E, De Flora A, Schenone A, Bruzzone S.

Dept. of Neurosciences, Ophtalmology and Genetics, and CEBR, University of

Genova, Italy;

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 peripheral myelin

protein-22 (PMP22) 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

([Ca2+]i) in SC from CMT1A rats. By the use of specific pharmacological

inhibitors and through down-regulation of expression by small interfering RNA

(siRNA), we demonstrate that the high [Ca2+]i is caused by a PMP22-related

overexpression of the P2X7 purinoceptor/channel leading to influx of

extracellular Ca2+ into CMT1A SC.

Correction of the altered [Ca2+]i in CMT1A SC by siRNA or with pharmacological

inhibitors of P2X7 restores functional parameters of SC (migration, 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 [Ca2+]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.