bims-mideyd 2022-08-14 papers

Cells. 2022 Aug 02. pii: 2386. [Epub ahead of print]11(15):

Nuclear Receptor Atlases of Choroidal Tissues Reveal Candidate Receptors Associated with Age-Related Macular Degeneration.

Jeremy Peavey, Vipul M Parmar, Goldis Malek.

The choroid is a vulnerable tissue site in the eye, impacted in several blinding diseases including age related macular degeneration (AMD), which is the leading cause of central vision loss in the aging population. Choroidal thinning and choriocapillary dropout are features of the early form of AMD, and endothelial dysfunction and vascular changes are primary characteristics of the neovascular clinical sub-type of AMD. Given the importance, the choroidal endothelium and outer vasculature play in supporting visual function, a better understanding of baseline choroidal signaling pathways engaged in tissue and cellular homeostasis is needed. Nuclear receptors are a large family of transcription factors responsible for maintaining various cellular processes during development, aging and disease. Herein we developed a comprehensive nuclear receptor atlas of human choroidal endothelial cells and freshly isolated choroidal tissue by examining the expression levels of all members of this transcription family using quantitative real time PCR. Given the close relationship between the choroid and retinal pigment epithelium (RPE), this data was cross-referenced with the expression profile of nuclear receptors in human RPE cells, to discover potential overlap versus cell-specific nuclear receptor expression. Finally, to identify candidate receptors that may participate in the pathobiology of AMD, we cataloged nuclear receptor expression in a murine model of wet AMD, from which we discovered a subset of nuclear receptors differentially regulated following neovascularization. Overall, these databases serve as useful resources establishing the influence of nuclear receptor signaling pathways on the outer vascular tissue of the eye, while providing a list of receptors, for more focused investigations in the future, to determine their suitability as potential therapeutic targets for diseases, in which the choroid is affected.

Keywords: age-related macular degeneration; choroidal endothelial cells; choroidal injury; nuclear receptor atlas

DOI: https://doi.org/10.3390/cells11152386

Molecules. 2022 Aug 04. pii: 4957. [Epub ahead of print]27(15):

A Small Natural Molecule S3 Protects Retinal Ganglion Cells and Promotes Parkin-Mediated Mitophagy against Excitotoxicity.

Dongli Zhuang, Rong Zhang, Haiyang Liu, Yi Dai.

Glutamate excitotoxicity may contribute to retinal ganglion cell (RGC) degeneration in glaucoma and other optic neuropathies, leading to irreversible blindness. Growing evidence has linked impaired mitochondrial quality control with RGCs degeneration, while parkin, an E3 ubiquitin ligase, has proved to be protective and promotes mitophagy in RGCs against excitotoxicity. The purpose of this study was to explore whether a small molecule S3 could modulate parkin-mediated mitophagy and has therapeutic potential for RGCs. The results showed that as an inhibitor of deubiquitinase USP30, S3 protected cultured RGCs and improved mitochondrial health against NMDA-induced excitotoxicity. Administration of S3 promoted the parkin expression and its downstream mitophagy-related proteins in RGCs. An upregulated ubiquitination level of Mfn2 and protein level of OPA1 were also observed in S3-treated RGCs, while parkin knockdown resulted in a major loss of the protective effect of S3 on RGCs under excitotoxicity. These findings demonstrated that S3 promoted RGC survival mainly through enhancing parkin-mediated mitophagy against excitotoxicity. The neuroprotective value of S3 in glaucoma and other optic neuropathies deserves further investigation.

Keywords: 15-oxospiramilactone; excitotoxicity; mitophagy; parkin; retinal ganglion cells

DOI: https://doi.org/10.3390/molecules27154957

Hum Mol Genet. 2022 Aug 09. pii: ddac187. [Epub ahead of print]

Complement factor B is critical for sub-RPE deposit accumulation in a model of Doyne honeycomb retinal dystrophy with features of age-related macular degeneration.

EFEMP1 R345W is a dominant mutation causing Doyne honeycomb retinal dystrophy/malattia leventinese (DHRD/ML), a rare blinding disease with clinical pathology similar to age-related macular degeneration (AMD). Aged Efemp1R345W/R345W knock-in mice (Efemp1ki/ki) develop microscopic deposits on the basal side of retinal pigment epithelial cells (RPE), an early feature in DHRD/ML and AMD. Here, we assessed the role of alternative complement pathway component factor B (FB) in the formation of these deposits. RNA-seq analysis of the posterior eyecups revealed increased unfolded protein response, decreased mitochondrial function in the neural retina (by 3 months of age), and increased inflammatory pathways in both neural retina and posterior eyecups (at 17 months of age) of Efemp1ki/ki mice compared with wild-type littermate controls. Proteomics analysis of eye lysates confirmed similar dysregulated pathways as detected by RNA-seq. Complement activation was increased in aged Efemp1ki/ki eyes with an approximately two-fold elevation of complement breakdown products iC3b and Ba (p < 0.05). Deletion of the Cfb gene in female Efemp1ki/ki mice partially normalized the above dysregulated biological pathway changes and oral dosing of a small molecule FB inhibitor from 10- to 12-months of age reduced sub-RPE deposits by 65% (p = 0.029). In contrast, male Efemp1ki/ki mice had fewer sub-RPE deposits than age-matched females, no elevation of ocular complement activation, and no effect of FB inhibition on sub-RPE deposits. The effects of FB deletion or inhibition on Efemp1ki/ki mice supports systemic inhibition of the alternative complement pathway as a potential treatment of dry AMD and DHRD/ML.

DOI: https://doi.org/10.1093/hmg/ddac187

Hum Mol Genet. 2022 Aug 10. pii: ddac190. [Epub ahead of print]

Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy.

Zhipeng Nie, Chenhui Wang, Jiarong Chen, Yanchun Ji, Hongxing Zhang, Fuxin Zhao, Xiangtian Zhou, Min-Xin Guan.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease that results from degeneration of retinal ganglion cells (RGC). Mitochondrial ND4 11778G > A mutation, which affects structural components of complex I, is the most prevalent LHON-associated mitochondrial DNA (mtDNA) mutation worldwide. The m.11778G > A mutation is the primary contributor underlying the development of LHON and X-linked PRICKLE3 allele (c.157C > T, p.Arg53Trp) linked to biogenesis of ATPase interacts with m.11778G > A mutation to cause LHON. However, the lack of appropriate cell and animal models of LHON has been significant obstacles for deep elucidation of disease pathophysiology, specifically the tissue specific effects. Using RGC-like cells differentiated from induced pluripotent stem cells (iPSCs) from members of one Chinese family (asymptomatic subjects carrying only m.11778G > A mutation or PRICKLE3 p.Arg53Trp mutation, symptomatic individuals bearing both m.11778G > A and PRICKLE3 p.Arg53Trp mutations and control lacking these mutations), we demonstrated the deleterious effects of mitochondrial dysfunctions on the morphology and functions of RGCs. Notably, iPSCs bearing only m.11778G > A or p.Arg53Trp mutation exhibited mild defects in differentiation to RGC-like cells. The RGC-like cells carrying only m.11778G > A or p.Arg53Trp mutation displayed mild defects in RGC morphology, including the area of soma and numbers of neurites, electrophysiological properties, ATP production and apoptosis. Strikingly, those RGC-like cells derived from symptomatic individuals harboring both m.11778G > A and p.Arg53Trp mutations displayed greater defects in the development, morphology and functions than those in cells bearing single mutation. These findings provide new insights into pathophysiology of LHON arising from RGC deficiencies caused by synergy between m.11778G > A and PRICKLE3 p.Arg53Trp mutation.

DOI: https://doi.org/10.1093/hmg/ddac190