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Peter Koulen; Presenilins control the intracellular calcium signaling and viability of retinal neurons. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5435.
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© ARVO (1962-2015); The Authors (2016-present)
The loss of visual function in optic neuropathies resulting from injury or chronic disease is characterized by the degeneration and cell death of retinal ganglion cells (RGCs). As the programmed cell death of RGCs in degenerative retinopathies is preceded by L-glutamate mediated excitotoxicity, subsequent cellular calcium dyshomeostasis and toxicity mediated by chronically elevated intracellular calcium concentrations, control of these signaling pathways has become the target of related therapy development efforts. Presenilin proteins, in addition to their function in the enzymatic processing of amyloid precursor protein, control the intracellular free calcium ion concentration by interaction with intracellular calcium release channels. The present study tested the hypothesis that modulation of the presenilin protein concentration in RGCs leads to protection against excitotoxicity.
Murine RGCs and retinal explants were isolated and cultured and their cellular viability was measured in response to chronic L-glutamate-mediated toxicity using immunocytochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. The concentration of presenilin 1 and 2 proteins in the cell cultures was altered using mammalian expression vectors and gene-specific small interfering RNA and determined with microfluorimetry. Changes in intracellular calcium signaling were measured using calcium imaging and pharmacological control of intracellular calcium channel activity.
Both presenilin 1 and 2 are expressed by RGCs. siRNA-mediated knockdown of presenilin 1 significantly (p<0.001) increased viability of both isolated cultured RGCs and of organotypic cultures by 43±9% and 59±12%, respectively. This was paralleled by statistically significantly (p<0.01) attenuated calcium release from intracellular stores at 38±12% and 46±17%, respectively. Overexpression of presenilin 1 elicited potentiated calcium release from intracellular stores and decreased viability of RGCs. Modulation of presenilin 2 generated similar responses.
Presenilins control calcium release from intracellular stores and thereby affect cellular viability as a function of cellular calcium dyshomeostasis following injury or resulting from disease processes. These mechanisms of action therefore represent novel potential targets for therapeutic intervention and drug development in optic neuropathies.
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