Identification of Redox and Glucose‐Dependent Txnip Protein Interactions

Forred, Benjamin J.; Neuharth, Skyla; Kim, Dae In; Amolins, Michael W.; Motamedchaboki, Khatereh; Roux, Kyle J.; Vitiello, Peter F.

doi:10.1155/2016/5829063

Cited by 17 publications

(8 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compared to the control cones without Txnip transduction, the intensity of mitoRFP was higher in P20 rd1 cones transduced with Txnip (Figure 5 -figure supplement 1C,D). A previous study identified 15 proteins that interact with Txnip.C247S (Forred et al, 2016). Among these interactors was Parp1, which can negatively affect mitochondria through deleterious effects on the mitochondrial genome (Hocsak et al, 2017;Szczesny et al, 2014), as well as effects on inflammation and other cellular pathways (Fehr et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

Xue

Wang

Rana

et al. 2021

eLife

View full text Add to dashboard Cite

Retinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a disease gene-agnostic therapy, we screened 20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

show abstract

Section: Resultsmentioning

confidence: 99%

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

Xue

Wang

Rana

et al. 2021

eLife

View full text Add to dashboard Cite

show abstract

“…5c,d). A previous study identified 15 proteins that interact with Txnip.C247S (Forred et al, 2016). Among these interactors was Parp1, which can negatively affect mitochondria through deleterious effects on the mitochondrial genome (Hocsak et al, 2017;Szczesny et al, 2014), as well as have effects on inflammation and other cellular pathways (Fehr et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

Xue

Wang

Rana

et al. 2021

Preprint

View full text Add to dashboard Cite

Retinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a gene-agnostic therapy, we screened ≈20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

show abstract

“…Another partner interaction suggested by previous studies and explored here is the interaction with HSP90AB1 ( Figure 5 ). HSP90AB1 interacts with both the wt and C247S alleles (Forred et al, 2016). Little is known about the function of HSP90AB1.…”

Section: Discussionmentioning

confidence: 99%

Txnip deletions and missense alleles prolong the survival of cones in a retinitis pigmentosa mouse model

Xue¹,

Cepko²

2023

Preprint

View full text Add to dashboard Cite

Retinitis pigmentosa (RP) is a prevalent inherited retinal degenerative disease worldwide, affecting 1 in 4,000 people. The disease is characterized by an initial loss of night vision followed by a loss of daylight and color vision. Many of the RP disease genes are expressed in the rod photoreceptors, the cell type that initiates dim light vision. Following loss of rods, the cone photoreceptors, which initiate daylight vision, also are affected and can die leading to total loss of vision. The reasons for loss of cone vision are not entirely clear, but appear to be due to loss of the rods. Previously we showed that overexpressing Txnip, an α-arrestin protein, in mouse models of RP using AAV gene therapy prolonged the survival of RP cones (Xue et al. 2021). At least part of the mechanism for cone survival was a switch in the fuel source, from glucose to lactate. In addition, the mitochondria of cones were both morphologically and functionally improved by delivery of Txnip. We have gone on to test several alleles of Txnip for the ability to prolong cone survival in rd1, a mouse model of RP. In addition, proteins that bind to Txnip and/or have homology to Txnip were tested. Five different deletions of Txnip were expressed in cones or the retinal pigmented epithelium (RPE). Here we show that the C-terminal half of Txnip (149-397aa) is sufficient to remove GLUT1 from the RPE cell surface, and improved rd1 cone survival when expressed specifically in the RPE. Overexpressing Arrdc4, an α-arrestin that shares 60% similar protein sequence to Txnip, reduced rd1 cone survival. Reduction of the expression of HSP90AB1, a protein that interacts with Txnip and regulates metabolism, improved the survival of rd1 cones alone and was additive for cone survival when combined with Txnip. However, full length Txnip with a single amino acid change, C247S, remains the most highly efficacious form of the gene for cone rescue. The above observations suggest that only a subset of the hypothesized and known activities of Txnip play a role in promoting RP cone survival, and that the activities of Txnip in the RPE differ from those in cone photoreceptors.

show abstract

Identification of Redox and Glucose‐Dependent Txnip Protein Interactions

Cited by 17 publications

References 41 publications

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

Txnip deletions and missense alleles prolong the survival of cones in a retinitis pigmentosa mouse model

Contact Info

Product

Resources

About