Light Induces Ultrastructural Changes in Rod Outer and Inner Segments, Including Autophagy, in a Transgenic<i>Xenopus laevis</i>P23H Rhodopsin Model of Retinitis Pigmentosa

Bogéa, Tami; Wen, Runxia; Moritz, Orson L.

doi:10.1167/iovs.15-16799

Cited by 30 publications

(43 citation statements)

References 57 publications

(75 reference statements)

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“…In summary, we demonstrated that mislocalized rhodopsin disrupts the PM homeostasis of rod photoreceptors through concomitant lysosome-mediated degradation of IS PM membrane protein, NKA. Lysosome-mediated degradation is associated with various photoreceptor degenerative disorders (Chen et al, 2013;Bogéa et al, 2015;Yao et al, 2018), but the context and consequences of the degradation differ among these diseases. For example, in a light-dependent photoreceptor degeneration model, activation of lysosomes and autophagy is neuroprotective (Chen et al, 2013), but in a mouse model of a class II rhodopsin gene mutation (Sakami et al, 2011(Sakami et al, , 2014, activation exacerbates the photoreceptor degeneration (Yao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Disrupted Plasma Membrane Protein Homeostasis in a Xenopus Laevis Model of Retinitis Pigmentosa

Ropelewski

Imanishi

2019

J. Neurosci.

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Rhodopsin mislocalization is frequently observed in retinitis pigmentosa (RP) patients. For example, class I mutant rhodopsin is deficient in the VxPx trafficking signal, mislocalizes to the plasma membrane (PM) of rod photoreceptor inner segments (ISs), and causes autosomal dominant RP. Mislocalized rhodopsin causes photoreceptor degeneration in a manner independent of light-activation. In this manuscript, we took advantage of Xenopus laevis models of both sexes expressing wild-type human rhodopsin or its class I Q344ter mutant fused to Dendra2 fluorescent protein to characterize a novel light-independent mechanism of photoreceptor degeneration caused by mislocalized rhodopsin. We found that rhodopsin mislocalized to the PM is actively internalized and transported to lysosomes where it is degraded. This degradation process results in the downregulation of a crucial component of the photoreceptor IS PM: the sodiumpotassium ATPase ␣-subunit (NKA␣). The downregulation of NKA␣ is not because of decreased NKA␣ mRNA, but due to cotransport of mislocalized rhodopsin and NKA␣ to lysosomes or autophagolysosomes. In a separate set of experiments, we found that class I mutant rhodopsin, which causes NKA␣ downregulation, also causes shortening and loss of rod outer segments (OSs); the symptoms frequently observed in the early stages of human RP. Likewise, pharmacological inhibition of NKA␣ led to shortening and loss of rod OSs. These combined studies suggest that mislocalized rhodopsin leads to photoreceptor dysfunction through disruption of the PM protein homeostasis and compromised NKA␣ function. This study unveiled a novel role of lysosome-mediated degradation in causing inherited disorders manifested by mislocalization of ciliary receptors. Significance StatementRetinal ciliopathy is the most common form of inherited blinding disorder frequently manifesting rhodopsin mislocalization. Our understanding of the relationships between rhodopsin mislocalization and photoreceptor dysfunction/degeneration has been far from complete. This study uncovers a hitherto uncharacterized consequence of rhodopsin mislocalization: the activation of the lysosomal pathway, which negatively regulates the amount of the sodium-potassium ATPase (NKA␣) on the inner segment plasma membrane. On the plasma membrane, mislocalized rhodopsin extracts NKA␣ and sends it to lysosomes where they are co-degraded. Compromised NKA␣ function leads to shortening and loss of the photoreceptor outer segments as observed for various inherited blinding disorders. In summary, this study revealed a novel pathogenic mechanism applicable to various forms of blinding disorders caused by rhodopsin mislocalization.

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Section: Discussionmentioning

confidence: 99%

Disrupted Plasma Membrane Protein Homeostasis in a Xenopus Laevis Model of Retinitis Pigmentosa

Ropelewski

Imanishi

2019

J. Neurosci.

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“…9 and 10). Aggresomes are also not observed in rod photoreceptor cells in adRP animal models expressing P23H opsin [20,52,53]. Thus, small aggregates are the likely toxic species rather than aggresomes.…”

Section: Discussionmentioning

confidence: 99%

Wild-type opsin does not aggregate with a misfolded opsin mutant

Gragg

Kim

Howell

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Rhodopsin is the light receptor in photoreceptor cells that plays a central role in phototransduction and photoreceptor cell health. Mutations in rhodopsin are the leading cause of autosomal dominant retinitis pigmentosa (adRP), a retinal degenerative disease. A majority of mutations in rhodopsin cause misfolding and aggregation of the apoprotein opsin. The pathogenesis of adRP caused by misfolded opsin is unclear. It has been proposed that physical interactions between wild-type opsin and misfolded opsin mutants may underlie the autosomal dominant phenotype. To test whether or not wild-type opsin can form a complex with misfolded opsin mutants, we examined the interactions between wild-type opsin and opsin with a G188R mutation, a clinically identified mutation causing adRP. Förster resonance energy transfer (FRET) was utilized to monitor the interactions between fluorescently tagged opsins expressed in live cells. The FRET assay employed was able to discriminate between properly folded opsin oligomers and misfolded opsin aggregates. Wild-type opsin predominantly formed oligomers and only a minor population formed aggregates. Conversely, the G188R opsin mutant predominantly formed aggregates. When wild-type opsin and G188R opsin were coexpressed in cells, properly folded wild-type opsin did not aggregate with G188R opsin and was trafficked normally to the plasma membrane. Thus, the autosomal dominant phenotype in adRP caused by misfolded opsin mutants is not predicted to arise from physical interactions between wild-type opsin and misfolded opsin mutants.

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“…In addition, autophagy has been found to regulate the ultrastructure and function of photoreceptors and to alter their survival and death [36,37]. Wang et al [38] found that inducing autophagy significantly suppressed light-induced photoreceptor death and photoreceptor neural degeneration through the turnover of toxic rhodopsin.…”

Section: Autophagy In Photoreceptorsmentioning

confidence: 99%

Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina

Lin

2018

Ophthalmic Res

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Autophagy is a lysosomal degradation process that maintains cellular homeostasis by removing dysfunctional organelles and unfolded proteins. Increasing evidence has shown that autophagy proteins are involved in retinal physiology and pathology and that defective autophagy contributes to retinal degeneration. In retinal diseases, autophagy plays a dual role: promoting retinal cell survival and death. Autophagy at a normal level helps retinal cells defend themselves against harmful stress; however, excessive autophagy results in retinal deterioration. Both synergistic and antagonistic roles of autophagy and apoptosis in the retina have been reported in the literature. In this review, we summarize the roles of autophagy in the development of the retina and retinal diseases. This review highlights the importance of autophagy in retinal diseases, and targeting autophagy may provide a new therapeutic approach for retinal diseases.

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Light Induces Ultrastructural Changes in Rod Outer and Inner Segments, Including Autophagy, in a TransgenicXenopus laevisP23H Rhodopsin Model of Retinitis Pigmentosa

Cited by 30 publications

References 57 publications

Disrupted Plasma Membrane Protein Homeostasis in a Xenopus Laevis Model of Retinitis Pigmentosa

Disrupted Plasma Membrane Protein Homeostasis in a Xenopus Laevis Model of Retinitis Pigmentosa

Wild-type opsin does not aggregate with a misfolded opsin mutant

Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina

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