Structural and functional impairment of endocytic pathways by retinitis pigmentosa mutant rhodopsin-arrestin complexes

Chuang, Jen-Zen; Vega, Carrie; Jun, Wenjin; Sung, Ching-Hwa

doi:10.1172/jci21136

Cited by 35 publications

(47 citation statements)

References 47 publications

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“…Although this may simply reflect general protein accumulation in photoreceptors, it would also be compatible with an involvement of calpains in the hydrolysis and/or trafficking of rhodopsin. Dysregulated arrestin breakdown, alone or in combination with effects on rhodopsin, could thus promote degeneration of photoreceptors in ways similar to those causing retinal degeneration via abnormal rhodopsin/arrestin complexes (Chuang et al. 2004; Chen et al.…”

Section: Discussionmentioning

confidence: 99%

Photoreceptor rescue and toxicity induced by different calpain inhibitors

Paquet-Durand¹,

Sanges²,

McCall³

et al. 2010

Journal of Neurochemistry

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J. Neurochem. (2010) 115, 930–940. Abstract Photoreceptor degeneration is the hallmark of a group of inherited blinding diseases collectively termed retinitis pigmentosa (RP); a major cause of blindness in humans. RP is at present untreatable and the underlying neurodegenerative mechanisms are largely unknown, even though the genetic causes are often established. The activation of calpain‐type proteases may play an important role in cell death in various neuronal tissues, including the retina. We therefore tested the efficacy of two different calpain inhibitors in preventing cell death in the retinal degeneration (rd1) human homologous mouse model for RP. Pharmacological inhibition of calpain activity in rd1 organotypic retinal explants had ambiguous effects on photoreceptor viability. Calpain inhibitor XI had protective effects when applied for short periods of time (16 h) but demonstrated substantial levels of toxicity in both wild‐type and rd1 retina when used over several days. In contrast, the highly specific calpain inhibitor calpastatin peptide reduced photoreceptor cell death in vitro after both short and prolonged exposure, an effect that was also evident after in vivo application via intravitreal injection. These findings highlight the importance of calpain activation for photoreceptor cell death but also for photoreceptor survival and propose the use of highly specific calpain inhibitors to prevent or delay RP.

show abstract

Section: Discussionmentioning

confidence: 99%

Photoreceptor rescue and toxicity induced by different calpain inhibitors

Paquet-Durand¹,

Sanges²,

McCall³

et al. 2010

Journal of Neurochemistry

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“…This study demonstrates the feasibility of a higher-throughput cell-based assay for the functional characterization of VUS in IRDs, compared to the standard approach of using a cellbased assay for each variant individually (Sung, 1993;Li, 1998;Chuang, 2004;Chen, 2011;Davies, 2012;Hollingsworth, 2013;Liu, 2013;McKeone, 2014;Yamasaki, 2014).…”

Section: Discussionmentioning

confidence: 89%

Characterizing variants of unknown significance in rhodopsin: a functional genomics approach

Wan

Place

Pierce

et al. 2019

Preprint

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Characterizing the pathogenicity of DNA sequence variants of unknown significance (VUS) is a major bottleneck in human genetics, and is increasingly important in determining which patients with inherited retinal diseases could benefit from gene therapy. A library of 210 rhodopsin (RHO) variants from literature and in‐house genetic diagnostic testing were created to efficiently detect pathogenic RHO variants that fail to express on the cell surface. This study, while focused on RHO, demonstrates a streamlined, generalizable method for detecting pathogenic VUS. A relatively simple next‐generation sequencing‐based readout was developed so that a flow cytometry‐based assay could be performed simultaneously on all variants in a pooled format, without the need for barcodes or viral transduction. The resulting dataset characterized the surface expression of every RHO library variant with a high degree of reproducibility (r2 = 0.92–0.95), recategorizing 37 variants. For example, three retinitis pigmentosa pedigrees were solved by identifying VUS which showed low expression levels (p.G18D, p.G101V, and p.P180T). Results were validated across multiple assays and correlated with clinical disease severity. This study presents a parallelized, higher‐throughput cell‐based assay for the functional characterization of VUS in RHO, and can be applied more broadly to other inherited retinal disease genes and other disorders.

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“…The R135L mutation causes rhodopsin hyperphosphorylation, arrestin binding and aberrant rhodopsin endocytosis ( Fig. 22.1a), which deleteriously affects vesicular traffic (Chuang et al 2004). Hsp90 inhibition blocked the recruitment of arrestin to R135L mutant rhodopsin and thereby alleviated aberrant endocytosis .…”

Section: Retinitis Pigmentosa (Rp)mentioning

confidence: 99%

Retinal Degenerative Diseases

2016

Advances in Experimental Medicine and Biology

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Structural and functional impairment of endocytic pathways by retinitis pigmentosa mutant rhodopsin-arrestin complexes

Cited by 35 publications

References 47 publications

Photoreceptor rescue and toxicity induced by different calpain inhibitors

Photoreceptor rescue and toxicity induced by different calpain inhibitors

Characterizing variants of unknown significance in rhodopsin: a functional genomics approach

Retinal Degenerative Diseases

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