ArticleTransactions of the American Ophthalmological Society2014
Silencing of tuberin enhances photoreceptor survival and function in a preclinical model of retinitis pigmentosa (an american ophthalmological society thesis).
Article in Transactions of the American Ophthalmological Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 13 citations in OpenAlex.
- Rapamycin Improved Retinal Function and Morphology in a Mouse Model of Retinal Degeneration.Frontiers in neuroscience · 2022Article
- Replenishment of TCA cycle intermediates provides photoreceptor resilience against neurodegeneration during progression of retinitis pigmentosa.JCI insight · 2021Article
- Inhibition of mTOR signaling by rapamycin protects photoreceptors from degeneration inZoological research · 2021Article
- Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations.Translational vision science & technology · 2020Article
- AKT3 Gene Transfer Promotes Anabolic Reprogramming and Photoreceptor Neuroprotection in a Pre-clinical Model of Retinitis Pigmentosa.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- Genetic Rescue Reverses Microglial Activation in Preclinical Models of Retinitis Pigmentosa.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Article
- Reprogramming the metabolome rescues retinal degeneration.Cellular and molecular life sciences : CMLS · 2018Review
- Peptide Arrays: Development and Application.Analytical chemistry · 2018Review
- Structural modeling of a novelMolecular genetics & genomic medicine · 2017Article
- Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration.The Journal of clinical investigation · 2016Article
- Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa.Human molecular genetics · 2016Article
- Rod metabolic demand drives progression in retinopathies.Taiwan journal of ophthalmologyReview
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
purposeTo assess the functional consequences of silencing of tuberin, an inhibitor of the mTOR signaling pathway, in a preclinical model of retinitis pigmentosa (RP) in order to test the hypothesis that insufficient induction of the protein kinase B (PKB)-regulated tuberin/mTOR self-survival pathway initiates apoptosis.
methodsIn an unbiased genome-scale approach, kinase peptide substrate arrays were used to analyze self-survival pathways at the onset of photoreceptor degeneration. The mutant Pde6b(H620Q)/Pde6b(H620Q) at P14 and P18 photoreceptor outer segment (OS) lysates were labeled with P-ATP and hybridized to an array of 1,164 different synthetic peptide substrates. At this stage, OS of Pde6b(H620Q)/Pde6b(H620Q) rods are morphologically normal. In vitro kinase assays and immunohistochemistry were used to validate phosphorylation. Short hairpin RNA (shRNA) gene silencing was used to validate tuberin's role in regulating survival.
resultsAt the onset of degeneration, 162 peptides were differentially phosphorylated. Protein kinases A, G, C (AGC kinases), and B exhibited increased activity in both peptide array and in vitro kinase assays. Immunohistochemical data confirmed altered phosphorylation patterns for phosphoinositide-dependent kinase-1 (PDK1), ribosomal protein S6 (RPS6), and tuberin. Tuberin gene silencing rescued photoreceptors from degeneration.
conclusionsPhosphorylation of tuberin and RPS6 is due to the upregulated activity of PKB. PKB/tuberin cell growth/survival signaling is activated before the onset of degeneration. Substrates of the AGC kinases in the PKB/tuberin pathway are phosphorylated to promote cell survival. Knockdown of tuberin, the inhibitor of the mTOR pathway, increased photoreceptor survival and function in a preclinical model of RP.
Indexed as
Identifiers
25646031PMC4311672W2186505887What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.