| First Author | Guo X | Year | 2014 |
| Journal | Am J Pathol | Volume | 184 |
| Issue | 4 | Pages | 1017-29 |
| PubMed ID | 24508229 | Mgi Jnum | J:208041 |
| Mgi Id | MGI:5560830 | Doi | 10.1016/j.ajpath.2013.12.012 |
| Citation | Guo X, et al. (2014) PGC-1alpha Signaling Coordinates Susceptibility to Metabolic and Oxidative Injury in the Inner Retina. Am J Pathol 184(4):1017-29 |
| abstractText | Retinal ganglion cells (RGCs), used as a common model of central nervous system injury, are particularly vulnerable to metabolic and oxidative damage. However, molecular mechanisms underlying this sensitivity have not been determined in vivo. PGC-1alpha (encoded by PPARGC1A) regulates adaptive metabolism and oxidative stress responses in a tissue- and cell-specific manner. Aberrant PGC-1alpha signaling is implicated in neurodegeneration, but the mechanism underlying its role in central nervous system injury remains unclear. We provide evidence from a mouse model that PGC-1alpha expression and activity are induced in adult retina in response to metabolic and oxidative challenge. Deletion of Ppargc1a dramatically increased RGC loss, in association with dysregulated expression of PGC-1alpha target metabolic and oxidative stress response genes, including Hmox1 (encoding HO-1), Tfam, and Vegfa. Vehicle-treated and naive Ppargc1a(-/-) mice also showed mild RGC loss, and surprisingly prominent and consistent retinal astrocyte reactivity. These cells critically regulate metabolic homeostasis in the inner retina. We show that PGC-1alpha signaling (not previously studied in glia) regulates detoxifying astrocyte responses to hypoxic and oxidative stresses. Finally, PGC-1alpha expression was modulated in the inner retina with age and in a model of chronic optic neuropathy. These data implicate PGC-1alpha signaling as an important regulator of astrocyte reactivity and RGC homeostasis to coordinate pathogenic susceptibility to metabolic and oxidative injury in the inner retina. |
