Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa.

Y Murakami,Kh Sonoda,T Ishibashi,J W Miller,Dg Vavvas,Y Ikeda,S Nakao,S Nakatake,K Fujiwara,S Notomi,T Tachibana,N Yoshida,T Hisatomi

doi:10.1038/cddiscovery.2015.58

Y Murakami, Kh Sonoda + Show 11 more

Open Access

https://doi.org/10.1038/cddiscovery.2015.58

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Journal: Cell death discovery	Publication Date: Nov 30, 2015
Citations: 25	License type: CC BY 4.0

Affiliation: Kyushu University, Akita University

Abstract

Retinitis pigmentosa (RP) refers to a group of inherited retinal degenerations resulting form rod and cone photoreceptor cell death. The rod cell death due to deleterious genetic mutations has been shown to occur mainly through apoptosis, whereas the mechanisms and features of the secondary cone cell death have not been fully elucidated. Our previous study showed that the cone cell death in rd10 mice, an animal model of RP, involves necrotic features and is partly mediated by the receptor interacting protein kinase. However, the relevancy of necrotic cone cell death in human RP patients remains unknown. In the present study, we showed that dying cone cells in rd10 mice exhibited cellular enlargement, along with necrotic changes such as cellular swelling and mitochondrial rupture. In human eyes, live imaging of cone cells by adaptive optics scanning laser ophthalmoscopy revealed significantly increased percentages of enlarged cone cells in the RP patients compared with the control subjects. The vitreous of the RP patients contained significantly higher levels of high-mobility group box-1, which is released extracellularly associated with necrotic cell death. These findings suggest that necrotic enlargement of cone cells is involved in the process of cone degeneration, and that necrosis may be a novel target to prevent or delay the loss of cone-mediated central vision in RP.

Highlights

Retinitis pigmentosa (RP), a major cause of hereditary blindness, is a heterogeneous group of inherited retinal degenerations resulting from rod and cone photoreceptor cell death
Rd10 mice develop progressive rod degeneration beginning around postnatal day 18 (P18), and only a slight proportion of rod cells remains at P28; the number of cone cells gradually decreases thereafter
Using biochemical and genetic techniques, we have previously shown that cone cell death occurs via receptor interacting protein (RIP) kinasemediated necrosis.[9]

Summary

Introduction

Retinitis pigmentosa (RP), a major cause of hereditary blindness, is a heterogeneous group of inherited retinal degenerations resulting from rod and cone photoreceptor cell death. As the loss of conemediated central and peripheral vision is the most debilitating aspect of RP, a better understanding of the mechanisms of cone cell death will be critical to developing novel therapeutics for this currently incurable disease. Apoptosis and necrosis are two major forms of cell death, defined by their morphological appearance.[4] Apoptosis is accompanied by the reduction of cellular volume and chromatin condensation, and necrosis is associated with cellular and organelle swelling and plasma membrane rupture. Necrosis was thought to be an unregulated form of cell death, it is known to have regulated components, such as those involving receptor interacting protein (RIP) kinases.[5,6]

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