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Editors Selection IGR 11-2
Neuroprotection: Calcineurin
Comment by Leonard A. Levin on:
13328 Calcineurin cleavage is triggered by elevated intraocular pressure, and calcineurin inhibition blocks retinal ganglion cell death in experimental glaucoma, Huang W; Fileta JB; Dobberfuhl A et al., Proceedings of the National Academy of Sciences of the United States of America, 2005; 102: 12242-12247
See also comment(s) by Manuel Vidal-Sanz •Huang et al. (41) report cleavage of the autoinhibitory domain of the protein phosphatase calcineurin (CaN) in two rodent models of increased IOP. Cleaved CaN was not detected in rat or mouse eyes with normal IOP. In in vitro systems, this constitutively active cleaved form of CaN has been reported to lead to apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member, Bad. In a rat model of glaucoma, they similarly detect increased Bad dephosphorylation, increased cytoplasmic cytochrome c (cyt c), and RGC death. Oral treatment of rats with increased IOP with the CaN inhibitor FK506 led to a reduction in Bad dephosphorylation and cyt c release.
A calcineurin inhibitor is neuroprotectiveThe results of Huang et al are important for several reasons, Firstly, they clearly show cleavage of total retinal calcineurin in experimental rodent glaucoma, but not in optic nerve transection. This means that not only is cleaved calcineurin a relatively specific finding in glaucomatous but not acute optic neuropathy. Furthermore, the finding that increased IOP virtually eliminates total retinal phosphorylated Bad and significantly reduces mitochondrial cytochrome c in their model implicates a process that involves more than just retinal ganglion cells. Finally, they saw significant neuroprotection of retinal ganglion cells and their axons with FK506 treatment, a calcineurin inhibitor, and although not proven, it is reasonable to believe that the neuroprotection is a result of the inhibition of calcineurin phosphatase activity.
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