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J. Biol. Chem., Vol. 283, Issue 52, 36377-36385, December 26, 2008

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Effect of -Synuclein Silencing on Apoptotic Pathways in Retinal Ganglion Cells^*

Irina Surgucheva, Valery I. Shestopalov^¶||, and Andrei Surguchov¹

From the Laboratory of Retinal Biology, Veterans Affairs Medical Center, Kansas City, Missouri 64128, the Department of Neurology, Kansas University Medical Center, Kansas City, Kansas 66160, the ^¶Bascom Palmer Eye Institute and the ^||Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida 33136

-Synuclein (Syn G) is highly expressed in retinal ganglion cells and the loss of these cells in glaucoma is associated with significant reduction of the intracellular Syn G level. However, a causative relationship between these two events has not been established. Here we show that the knockdown of Syn G results in a decreased viability of the immortalized retinal ganglion cells (RGC-5). The Syn G silencing reduces phosphorylation of serine 112 (Ser¹¹²) in Bad protein, a member of the Bcl-2 family that plays a critical role in apoptotic cell death signaling. Our gene expression analysis data suggests that changes in Bad phosphorylation status may be caused by a coordinated shift in activities of kinases controlling Bad phosphorylation and phosphatases catalyzing its dephosphorylation. Moreover, increased phosphorylation of Bad-sequestering protein 14-3-3 detected in these cells is also pro-apoptotic. These results suggest that the homeostatic level of Syn G in RGC-5 cells is required for transcriptional regulation of protein kinases and phosphatases, controlling phosphorylation of Bad and 14-3-3. Lowering Syn G causes Bad dephosphorylation, dissociation from phosphorylated 14-3-3, and translocation to mitochondria where it initiates apoptotic death cascade.

Received for publication, August 27, 2008 , and in revised form, October 15, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants EY02687, EY017991, and Center Grant P30 EY014801. This work was also supported by a Veterans Affairs Merit Review grant, The Glaucoma Foundation, Midwest Biomedical Research Foundation (MBRF), and an unrestricted grant to the University of Miami Department of Ophthalmology from Research to Prevent Blindness. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental Table.

¹ To whom correspondence should be addressed: Laboratory of Retinal Biology, Veterans Administration Medical Center, KS City, MO, 4801 Linwood Blvd., KS City, MO 64128. Tel.: 816-861-4700 (ext. 57078); Fax: 816-861-1110; E-mail: asurguchov{at}kumc.edu.

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