Joseph Hanna, Yacine Touahri, Alissa Pak, Luke Ajay David, Edwin van Oosten, Rajiv Dixit, Laura M Vecchio, Dhruv Nimesh Mehta, Ren Minamisono, Isabelle Aubert, Carol Schuurmans
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引用次数: 0
Abstract
Purpose: Silencing Phosphatase and tensin homolog (Pten) is a proposed therapeutic strategy for tissue regeneration to treat neurological disorders. However, Pten is pleiotropic, inhibiting several signaling and metabolic pathways, including mTORC1 and glycolysis, both pro-regenerative in certain contexts. This study aims to assess the long-term impact of inactivating Pten on photoreceptor survival in the retina and to identify downstream pathway(s).
Methods: We assessed retinal integrity in Pten conditional knock-outs (cKOs) that were retinal progenitor cell (RPC)-specific (Pten RPC-cKO), a congenital model, or rod-specific (Pten Rho-cKO). We examined early changes in photoreceptor gene expression and used immunostaining to assess photoreceptors, reactive astrocytes, microglia, angiogenesis, and subretinal deposit formation from postnatal day (P) 21 to 1 year of age. Pten RPC-cKO retinal explants were treated with rapamycin, an mTOR inhibitor, or 2-deoxy-D-glucose (2DG), a glycolysis inhibitor.
Results: In both Pten-cKO models, retinas display signs of early pathogenesis as photoreceptor-specific gene expression is downregulated at P0, before photoreceptor loss. Pten loss triggers progressive rod and cone degeneration beginning at P21 in Pten RPC-cKOs and at 6 months of age in Pten Rho-cKOs. Activated microglia and astrocytes, and increased angiogenesis, are observed in both Pten-cKO models, while subretinal amyloid-β deposits develop in Pten RPC-cKOs. Rapamycin accelerates photoreceptor degeneration in Pten RPC-cKOs, whereas 2DG has no effect.
Conclusions: Our findings suggest that Pten loss, either in RPCs as a congenital model, or solely in mature rod photoreceptors, leads to progressive retinal degeneration that is exacerbated by mTORC1 suppression, drawing into question the therapeutic value of Pten-mTORC1 manipulations.
期刊介绍:
Investigative Ophthalmology & Visual Science (IOVS), published as ready online, is a peer-reviewed academic journal of the Association for Research in Vision and Ophthalmology (ARVO). IOVS features original research, mostly pertaining to clinical and laboratory ophthalmology and vision research in general.