Rhodopsin Oligomerization and Aggregation

Park, Paul S.‐H.

doi:10.1007/s00232-019-00078-1

Cited by 23 publications

(16 citation statements)

References 118 publications

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“…In Drosophila, RHO mutants can recruit WT RHO into intracellular aggregates (62)(63)(64). In contrast to that, recent studies suggest that in mammalian cells, misfolded RHO P23H does not aggregate with properly folded RHO WT (65,66), although other evidence does suggest there is a dominant-negative effect of RHO P23H on the WT protein (2, 67).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration

Ueffing

Sen

Guarascio

et al. 2020

Preprint

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Due to continuously high production rates of rhodopsin (RHO) and high metabolic activity, photoreceptor neurons are especially vulnerable to defects in proteostasis. A proline to histidine substitution at position 23 (P23H) leads to production of structurally misfolded RHO, causing the most common form of autosomal dominant Retinitis Pigmentosa (adRP) in North America. The AAA-ATPase valosin-containing protein (VCP) extracts misfolded proteins from the ER membrane for cytosolic degradation. Here, we provide the first evidence that inhibition of VCP activity rescues degenerating P23H rod cells and improves their functional properties in P23H transgenic rat and P23H knock-in mouse retinae, both in vitro and in vivo. This improvement correlates with the restoration of the physiological RHO localization to rod outer segments (OS) and properly-assembled OS disks. As a single intravitreal injection suffices to deliver a long-lasting benefit in vivo, we suggest VCP inhibition as a potential therapeutic strategy for adRP patients carrying mutations in the RHO gene.

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Section: Discussionmentioning

confidence: 99%

Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration

Ueffing

Sen

Guarascio

et al. 2020

Preprint

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“…2). Misfolded GPCRs may even aggregate and accumulate, causing cell death (Park, 2019) and convergent phenotypes summarized as protein aggregate diseases (Aguzzi and O'Connor, 2010). One example is retinitis pigmentosa, in which rod photoreceptor cells degenerate because of deposits of misfolded mutant RHO (Miller et al, 2015).…”

Section: Inactivating Mutations Of Gpcrsmentioning

confidence: 99%

Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches

Schöneberg¹,

Liebscher²

2020

Pharmacol Rev

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There are approximately 800 annotated G protein-coupled receptor (GPCR) genes, making these membrane receptors members of the most abundant gene family in the human genome. Besides being involved in manifold physiologic functions and serving as important pharmacotherapeutic targets, mutations in 55 GPCR genes cause about 66 inherited monogenic diseases in humans. Alterations of nine GPCR genes are causatively involved in inherited digenic diseases. In addition to classic gain-and loss-of-function variants, other aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, pseudogenes, gene fusion, and gene dosage, contribute to the repertoire of GPCR dysfunctions. However, the spectrum of alterations and GPCR involvement is probably much larger because an additional 91 GPCR genes contain homozygous or hemizygous loss-of-function mutations in human individuals with currently unidentified phenotypes. This review highlights the complexity of genomic alteration of GPCR genes as well as their functional consequences and discusses derived therapeutic approaches. Significance Statement-With the advent of new transgenic and sequencing technologies, the number of monogenic diseases related to G protein-coupled receptor (GPCR) mutants has significantly increased, and our understanding of the functional impact of certain kinds of mutations has substantially improved. Besides the classical gain-and loss-of-function alterations, additional aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, uniparental disomy, pseudogenes, gene fusion, and gene dosage, need to be elaborated in light of GPCR dysfunctions and possible therapeutic strategies.

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“…Although normally some non-native interactions with other molecules may occur during the folding process (to bury highly aggregation-prone regions), conformationally abnormal proteins may aggregate provoking intra-and/or extracellular cellular protein accumulation with amyloid deposition as occurs in neurodegenerative diseases [2,14,15]. In the case of GPCRs, aggregation of misfolded proteins, as observed in neurodegenerative disorders, has been well documented only for a few misfolded GPCRs, mainly rhodopsin, in which toxic aggregates lead to retinal degeneration and disease [16,17]. In the past two decades, extraordinary efforts have been made to elucidate the molecular physiopathogenesis of diseases due to defective protein folding and to design potential therapeutic strategies that could prevent or correct the structural abnormality of disease-causing misfolded proteins [9,[18][19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects

Ulloa‐Aguirre

Zariñán

Jardón-Valadez

2021

IJMS

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Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.

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Rhodopsin Oligomerization and Aggregation

Cited by 23 publications

References 118 publications

Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration

Inhibition of VCP preserves retinal structure and function in autosomal dominant retinal degeneration

Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches

Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects

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