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Rossella Russo, Giuseppe P. Varano, Annagrazia Adornetto, Federica Cavaliere, Luigi A. Morrone, Maria Tiziana Corasaniti, Giacinto Bagetta; Retinal Ischemia Induces Deregulation of Basal Autophagy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2698.
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Autophagy is the major intracellular degradation pathway that regulates long-lived proteins and organelles turnover. This process occurs at basal levels in all cells but it is rapidly upregulated in response to starvation and cellular stress (Mizushima et al., 2008, Nature 28:1069-75). Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear (see Nixon, 2006, Trends Neurosci. 29:528-35). In this study we investigated the role of autophagy in retinal ganglion cell death following transient retinal ischemia, a common feature of ocular pathologies including glaucoma, anterior ischemic optic neuropathy and retinal vessels occlusion (see Osborne et al., 2004, Eye 18:1075-1084).
Retinal ischemia was induced in the right eye of adult male Wistar rat by acutely increasing the intraocular pressure (IOP). Expression of autophagy related proteins (Atg) was studied by western blotting and immunofluorescence. Effect of autophagy on RGC survival was evaluated in serum-starved RGC-5. NMDA antagonists, calpain inhibitors or siRNA were administered intravitreally.
Beclin-1 is involved in the early steps of autophagy vesicle formation whereas the ubiquitin-like conjugation system LC3 (microtubule-associated protein light chain 3) acts during autophagosome formation. Retinal ischemia was associated with a reduction of the phosphatidylethanolamine-modified form of LC3 (LC3II) and induced a significant decrease of beclin-1 expression. The latter event was associated with a proteolytic cleavage of beclin-1 that was prevented by the intravitreal treatment with the NMDA antagonist, MK801, the calpain inhibitor MDL28170 or by calpain siRNA. Inhibition of autophagy or Beclin-1 silencing in RGC-5 cells worsened cell loss under serum starvation conditions.
Altogether our results reveal that retinal ischemia induces a deregulation of basal autophagy and provide, for the first time, in vivo evidence of calpain-mediated cleavage of beclin-1. Furthermore, in vitro data support a neuroprotective role of autophagy in RGC-5.
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