Drug Discovery Strategies for Inherited Retinal Degenerations

Das, Arupratan; Imanishi, Yoshikazu

doi:10.3390/biology11091338

Cited by 5 publications

(3 citation statements)

References 209 publications

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“…However, it mislocalizes within rod cells 9 . As rhodopsin mislocalization is a phenomenon observed across a wide range of patients with RP and retinal ciliopathies, 6 this model is well‐suited for evaluating potential treatments aimed at mitigating rod degeneration in RP 70 . As previously reported for the Xenopus laevis model, 39,55 our research also confirms that murine rod cells possess a mechanism to reduce the levels of the mutated Q344X rhodopsin more effectively, surpassing the efficiency of the standard RPE‐mediated phagocytic process.…”

Section: Discussionmentioning

confidence: 99%

Rhodopsin mislocalization drives ciliary dysregulation in a novel autosomal dominant retinitis pigmentosa knock‐in mouse model

Takita,

Jahan,

S. Imanishi

et al. 2024

The FASEB Journal

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Rhodopsin mislocalization encompasses various blind conditions. Rhodopsin mislocalization is the primary factor leading to rod photoreceptor dysfunction and degeneration in autosomal dominant retinitis pigmentosa (adRP) caused by class I mutations. In this study, we report a new knock‐in mouse model that harbors a class I Q344X mutation in the endogenous rhodopsin gene, which causes rod photoreceptor degeneration in an autosomal dominant pattern. In RhoQ344X/+ mice, mRNA transcripts from the wild‐type (Rho) and RhoQ344X mutant rhodopsin alleles are expressed at equal levels. However, the amount of RHOQ344X mutant protein is 2.7 times lower than that of wild‐type rhodopsin, a finding consistent with the rapid degradation of the mutant protein. Immunofluorescence microscopy indicates that RHOQ344X is mislocalized to the inner segment and outer nuclear layers of rod photoreceptors in both RhoQ344X/+ and RhoQ344X/Q344X mice, confirming the essential role of the C‐terminal VxPx motif in promoting OS delivery of rhodopsin. The mislocalization of RHOQ344X is associated with the concurrent mislocalization of wild‐type rhodopsin in RhoQ344X/+ mice. To understand the global changes in proteostasis, we conducted quantitative proteomics analysis and found attenuated expression of rod‐specific OS membrane proteins accompanying reduced expression of ciliopathy causative gene products, including constituents of BBSome and axonemal dynein subunit. Those studies unveil a novel negative feedback regulation involving ciliopathy‐associated proteins. In this process, a defect in the trafficking signal leads to a reduced quantity of the trafficking apparatus, culminating in a widespread reduction in the transport of ciliary proteins.

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Section: Discussionmentioning

confidence: 99%

Rhodopsin mislocalization drives ciliary dysregulation in a novel autosomal dominant retinitis pigmentosa knock‐in mouse model

Takita,

Jahan,

S. Imanishi

et al. 2024

The FASEB Journal

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“…Several ocular diseases are linked to retinal cell loss, and diseases such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and diabetic retinopathy (DR) are characterized by photoreceptor degeneration; however, optic neuropathies, such as glaucoma, also lead to vision loss owing to retinal ganglion cell (RGC) loss [7].…”

Section: Introductionmentioning

confidence: 99%

Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives

Rosa,

Disner,

Pinto

et al. 2023

IJMS

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Visual impairment and blindness are a growing public health problem as they reduce the life quality of millions of people. The management and treatment of these diseases represent scientific and therapeutic challenges because different cellular and molecular actors involved in the pathophysiology are still being identified. Visual system components, particularly retinal cells, are extremely sensitive to genetic or metabolic alterations, and immune responses activated by local insults contribute to biological events, culminating in vision loss and irreversible blindness. Several ocular diseases are linked to retinal cell loss, and some of them, such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and diabetic retinopathy, are characterized by pathophysiological hallmarks that represent possibilities to study and develop novel treatments for retinal cell degeneration. Here, we present a compilation of revisited information on retinal degeneration, including pathophysiological and molecular features and biochemical hallmarks, and possible research directions for novel treatments to assist as a guide for innovative research. The knowledge expansion upon the mechanistic bases of the pathobiology of eye diseases, including information on complex interactions of genetic predisposition, chronic inflammation, and environmental and aging-related factors, will prompt the identification of new therapeutic strategies.

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“…Oxidative phosphorylation (OXPHOS) in mitochondria is the primary source for cellular ATP, thus mitochondrial dysfunction often associates with the neurodegenerative diseases such as mitochondrial optic neuropathies 2 , Parkinson's disease, and amyotrophic lateral sclerosis 4 . Among CNS neurons, retinal ganglion cells (RGCs) of the optic nerve require a steady source of ATP for their varying action potential firing frequency requirements and due to the existence of long partially unmyelinated axons 5 . Axons of human RGCs remain unmyelinated after leaving the cell body in the retinal layer as they travel through the optic nerve head, until they reach the posterior end of lamina cribrosa 6 .…”

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confidence: 99%

Enhanced mitochondrial biogenesis promotes neuroprotection in human pluripotent stem cell derived retinal ganglion cells

et al. 2023

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Mitochondrial dysfunctions are widely afflicted in central nervous system (CNS) disorders with minimal understanding on how to improve mitochondrial homeostasis to promote neuroprotection. Here we have used human stem cell differentiated retinal ganglion cells (hRGCs) of the CNS, which are highly sensitive towards mitochondrial dysfunctions due to their unique structure and function, to identify mechanisms for improving mitochondrial quality control (MQC). We show that hRGCs are efficient in maintaining mitochondrial homeostasis through rapid degradation and biogenesis of mitochondria under acute damage. Using a glaucomatous Optineurin mutant (E50K) stem cell line, we show that at basal level mutant hRGCs possess less mitochondrial mass and suffer mitochondrial swelling due to excess ATP production load. Activation of mitochondrial biogenesis through pharmacological inhibition of the Tank binding kinase 1 (TBK1) restores energy homeostasis, mitigates mitochondrial swelling with neuroprotection against acute mitochondrial damage for glaucomatous E50K hRGCs, revealing a novel neuroprotection mechanism.

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Drug Discovery Strategies for Inherited Retinal Degenerations

Cited by 5 publications

References 209 publications

Rhodopsin mislocalization drives ciliary dysregulation in a novel autosomal dominant retinitis pigmentosa knock‐in mouse model

Rhodopsin mislocalization drives ciliary dysregulation in a novel autosomal dominant retinitis pigmentosa knock‐in mouse model

Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives

Enhanced mitochondrial biogenesis promotes neuroprotection in human pluripotent stem cell derived retinal ganglion cells

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