Effect of gamma-synuclein silencing on apoptotic pathways in retinal ganglion cells.

Abstract

gamma-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.

• Authors: Irina Surgucheva, Valery I Shestopalov, Andrei Surguchov
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 52 Pg. 36377-85 (Dec 26 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18936092 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 14-3-3 Proteins
• Bad protein, rat
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• bcl-Associated Death Protein
• gamma-Synuclein

Topics

• 14-3-3 Proteins (metabolism)
• Animals
• Apoptosis
• Base Sequence
• Cell Survival
• Gene Silencing
• Mitochondria (metabolism)
• Molecular Sequence Data
• Phosphorylation
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA, Small Interfering (metabolism)
• Rats
• Retinal Ganglion Cells (metabolism)
• bcl-Associated Death Protein (metabolism)
• gamma-Synuclein (genetics, physiology)