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Jeremy Sivak, Xiaoxin Guo, Shirin Dason, Adrian Nahirny; PGC-1alpha Signaling Regulates Retinal Ganglion Cell Injury Responses And Atrocyte Reactivity. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4005.
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Glaucomatous optic neuropathy is associated with a complex combination of risk factors, including age, increased intraocular pressure, and vascular disregulation. These stresses converge to damage the sensitive nerve fiber layer (NFL), and optic nerve head, resulting in the death of retinal ganglion cells (RGCs). However, a molecular mechanism has not yet been identified that integrates local tissue responses to these varied insults. We have generated data identifying the transcriptional co-activator, PGC-1α (peroxisome proliferator-activated receptor gamma co-activator 1 alpha), as a potential key mediator of this process. When activated, PGC-1α interacts with transcription factors regulating metabolic, oxidative, and ischemic stress. Through these interactions PGC-1α acts as a master cellular regulator of adaptive energy metabolism.
Expression of PGC-1α was analyzed in acute and chronic mouse retinal injury models by quantitative rt-PCR, and in-situ hybridization. Putative PGC-1α targets, markers of metabolic and oxidative stress, glial reactivity, and RGC death were assessed by rt-PCR, immunofluorescence microscopy, and TUNEL assay, in combination with loss- and gain-of-function techniques.
PGC-1α expression was increased in RGCs and the NFL with age, and in a model of chronic ocular hypertension, as well as following acute excitotoxic retinal injury. PGC-1α loss-of-function resulted in significantly increased retinal astrocyte reactivity, and sensitivity of RGCs to damage, while increased activity was protective against oxidative stress.
We have identified an important pathway that can integrate retinal damage responses common to a variety of pathologically relevant insults.
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