Transducin β-Subunit Can Interact with Multiple G-Protein γ-Subunits to Enable Light Detection by Rod Photoreceptors

Dexter, Paige M.; Lobanova, Ekaterina S.; Finkelstein, Stella; Spencer, William J.; Skiba, Nikolai P.; Arshavsky, Vadim Y.

doi:10.1523/eneuro.0144-18.2018

Cited by 6 publications

(13 citation statements)

References 32 publications

(63 reference statements)

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“…We used imaging processing to quantify the number of nuclei within both the ONL and INL in these sections. This method has been utilized to characterize retinal degeneration in other animals 31, 32. Our results confirmed the conclusion of the SD-OCT analysis that there was no statistically significant difference in the number of photoreceptor nuclei within the ONL of our specimens from the two treatment groups (Figures 8A and 8B).…”

Section: Resultssupporting

confidence: 87%

Expression of a CARD Slows the Retinal Degeneration of a Geographic Atrophy Mouse Model

Young

Jones

Massengill

et al. 2019

Molecular Therapy - Methods & Clinical Development

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Age-related macular degeneration (AMD) has been linked to oxidative damage and para-inflammation, an activation of inflammasome signaling in the retinal pigment epithelium (RPE) and the underlying choriocapillaris. Herein, we tested the efficacy of a gene-delivered caspase-1 inhibitor in controlling the retinal degeneration observed in two models of RPE-choroid oxidative damage. In an acute model of oxidative stress (NaIO3 injection), eyes pre-treated with the sGFP-TatCARD (trans-activator of transcription; caspase activation and recruitment domain) vector demonstrated a recovery of retinal function and partial protection of RPE structure 1 month after damage, in contrast with control-treated eyes. In a model of chronic oxidative stress (RPE-specific deletion of Sod2 ), eyes treated with the sGFP-TatCARD vector after the onset of degeneration had a significantly slower decline in retinal function when compared to control-treated eyes. Earlier treatment of this model with the same adeno-associated virus (AAV) vector resulted in a greater protection of RPE function in eyes treated with the TatCARD when compared to control-treated eyes. Our results demonstrate that intravitreal delivery of sGFP-TatCARD reduces inflammation and can protect the retina from both acute and sustained oxidative damage within the RPE and choroid. Therefore, gene therapy with a cell-penetrating inflammasome inhibitor such as CARD may stem the progression of AMD.

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Section: Resultssupporting

confidence: 87%

Expression of a CARD Slows the Retinal Degeneration of a Geographic Atrophy Mouse Model

Young

Jones

Massengill

et al. 2019

Molecular Therapy - Methods & Clinical Development

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“…four-week-old mice, in which photoreceptor degeneration has just begun. As reported previously (Lobanova et al, 2013(Lobanova et al, , 2018Dexter et al, 2018), Ub G76V -GFP accumulated in retinas of both G␥ 1 -/and P23H mice ( Fig. 2A).…”

Section: Resultssupporting

confidence: 89%

“…Recent work has established that proteostatic stress, consisting of an insufficient capacity of the UPS to degrade proteasomal substrates, is a major contributing factor in multiple forms of inherited retinal degeneration (Lobanova et al, 2013;Liu et al, 2014;Dexter et al, 2018). In this study, we evaluated whether this proteostatic stress may originate from insufficient P97dependent substrate processing, which is required for the proteasomal degradation of a large number of UPS targets.…”

Section: Discussionmentioning

confidence: 99%

“…These conditions originate from mutations in Ͼ300 genes (https://sph.uth.edu/retnet/), many of which cause protein misfolding in affected photoreceptors. Previous work in multiple mouse models of retinal degeneration has indicated that the requirement to process large amounts of these misfolded proteins causes proteostatic stress, consisting of an insufficient capacity of the ubiquitin-proteasome system (UPS) to degrade proteasome substrates (Lobanova et al, 2013;Liu et al, 2014;Dexter et al, 2018). Conversely, genetic manipulation reducing the proteolytic capacity of proteasomes evokes photoreceptor death in otherwise normal retinas (Ando et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Previously, proteostatic stress in these mouse models was demonstrated using the proteasomal activity reporter Ub G76V -GFP (Dantuma et al, 2000), which accumulated robustly in degenerating G␥ 1 -/and P23H rods (Lobanova et al, 2013(Lobanova et al, , 2018Dexter et al, 2018). Because Ub G76V -GFP degradation by proteasomes requires its partial unfolding by P97 complexes (Wójcik et al, 2006;Beskow et al, 2009;Blythe et al, 2017), Ub G76V -GFP accumulation in these cells could indicate insufficient capacities of either of these UPS components.…”

Section: Introductionmentioning

confidence: 99%

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Probing Proteostatic Stress in Degenerating Photoreceptors Using Two ComplementaryIn VivoReporters of Proteasomal Activity

Dexter

Lobanova

Finkelstein

et al. 2019

eNeuro

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Inherited retinal degenerations originate from mutations in Ͼ300 genes, many of which cause the production of misfolded mutant photoreceptor proteins that are ultimately degraded by the ubiquitin-proteasome system (UPS). It was previously shown that rod photoreceptors in multiple mouse models of retinal degeneration suffer from proteostatic stress consisting of an insufficient cellular capacity for degrading UPS substrates. In this study, we focused on a specific UPS component required for the degradation of a subset of proteasome targets: the substrate-processing complex formed by the AAAϩ ATPase P97/VCP and associated cofactors. To assess whether P97 capacity may be insufficient in degenerating rods, we employed two complementary in vivo proteasomal activity reporters whose degradation is either P97-dependent or P97-independent. Retinal accumulation of each reporter was measured in two models of retinal degeneration: the transducin ␥-subunit knockout (G␥ 1-/-) and P23H rhodopsin knock-in (P23H) mice. Strikingly, the patterns of reporter accumulation differed between these models, indicating that the proteostatic stress observed in G␥ 1-/and P23H rods likely originates from different pathobiological mechanisms, in which UPS substrate degradation may or may not be limited by P97-dependent substrate processing. Further, we assessed whether P97 overexpression could ameliorate pathology in G␥ 1-/mice, in which proteostatic stress appears to result from P97 insufficiency. However, despite P97 overexpression being aphenotypic in other tissues, the ϳ2.4-fold increase in retinal P97 content was toxic to rods, which complicated the interpretation of the observed phenotype. Our results highlight the complexity of pathophysiological mechanisms related to degrading misfolded proteins in mutant photoreceptors.

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AAA+ Protein-Based Technologies to Counter Neurodegenerative Disease

March

Mack

Shorter

2019

Biophysical Journal

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Protein misfolding and overloaded proteostasis networks underlie a range of neurodegenerative diseases. No cures exist for these diseases, but developing effective therapeutic agents targeting the toxic, misfolded protein species in disease is one promising strategy. AAAþ (ATPases associated with diverse cellular activities) protein translocases, which naturally unfold and translocate substrate proteins, could be potent therapeutic agents to disassemble toxic protein conformers in neurodegenerative disease. Here, we discuss repurposing AAAþ protein translocases Hsp104 and proteasome-activating nucleotidase (PAN) to alleviate the toxicity from protein misfolding in neurodegenerative disease. Hsp104 effectively protects various animal models from neurodegeneration underpinned by protein misfolding, and enhanced Hsp104 variants strongly counter neurodegenerative disease-associated protein misfolding toxicity in yeast, Caenorhabditis elegans, and mammalian cells. Similarly, a recently engineered PAN variant (PAN et ) mitigates photoreceptor degeneration instigated by protein misfolding in a mouse model of retinopathy. Further study and engineering of AAAþ translocases like Hsp104 and PAN will reveal promising agents to combat protein misfolding toxicity in neurodegenerative disease.

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Transducin β-Subunit Can Interact with Multiple G-Protein γ-Subunits to Enable Light Detection by Rod Photoreceptors

Abstract: Visual Overview

Cited by 6 publications

References 32 publications

Expression of a CARD Slows the Retinal Degeneration of a Geographic Atrophy Mouse Model

Expression of a CARD Slows the Retinal Degeneration of a Geographic Atrophy Mouse Model

Probing Proteostatic Stress in Degenerating Photoreceptors Using Two ComplementaryIn VivoReporters of Proteasomal Activity

AAA+ Protein-Based Technologies to Counter Neurodegenerative Disease

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