Dataset Information

Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency.

ABSTRACT:

Purpose

Photoreceptor degeneration in the retina is a major cause of blindness in humans. Elucidating mechanisms of degenerative and neuroprotective pathways in photoreceptors should afford identification and development of therapeutic strategies.

Methods

We used mouse genetic models and improved methods for retinal explant cultures. Retinas were enucleated from Mef2d+/+ and Mef2d-/- mice, stained for MEF2 proteins and outer nuclear layer thickness, and assayed for apoptotic cells. Chromatin immunoprecipitation (ChIP) assays revealed MEF2 binding, and RT-qPCR showed levels of transcription factors. We used AAV2 and electroporation to express genes in retinal explants and electroretinograms to assess photoreceptor functionality.

Results

We identify a prosurvival MEF2D-PGC1? pathway that plays a neuroprotective role in photoreceptors. We demonstrate that Mef2d-/- mouse retinas manifest decreased expression of PGC1? and increased photoreceptor cell loss, resulting in the absence of light responses. Molecular repletion of PGC1? protects Mef2d-/- photoreceptors and preserves light responsivity.

Conclusions

These results suggest that the MEF2-PGC1? cascade may represent a new therapeutic target for drugs designed to protect photoreceptors from developmental- and age-dependent loss.

SUBMITTER: Nagar S

PROVIDER: S-EPMC5525556 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency.

Nagar Saumya S Trudler Dorit D McKercher Scott R SR Piña-Crespo Juan J Nakanishi Nobuki N Okamoto Shu-Ichi SI Lipton Stuart A SA

Investigative ophthalmology & visual science 20170701 9

<h4>Purpose</h4>Photoreceptor degeneration in the retina is a major cause of blindness in humans. Elucidating mechanisms of degenerative and neuroprotective pathways in photoreceptors should afford identification and development of therapeutic strategies.<h4>Methods</h4>We used mouse genetic models and improved methods for retinal explant cultures. Retinas were enucleated from Mef2d+/+ and Mef2d-/- mice, stained for MEF2 proteins and outer nuclear layer thickness, and assayed for apoptotic cells ...[more]

PMID: 28738418

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Project description:ImportanceSensitive outcome measures for disease progression are needed for treatment trials in geographic atrophy (GA) secondary to age-related macular degeneration (AMD).ObjectiveTo quantify photoreceptor degeneration outside regions of GA in eyes with nonexudative AMD, to evaluate its association with future GA progression, and to characterize its spatio-temporal progression.Design, setting, and participantsMonocenter cohort study (Directional Spread in Geographic Atrophy [NCT02051998]) and analysis of data from a normative data study at a tertiary referral center. One hundred fifty-eight eyes of 89 patients with a mean (SD) age of 77.7 (7.1) years, median area of GA of 8.87 mm2 (IQR, 4.09-15.60), and median follow-up of 1.1 years (IQR, 0.52-1.7 years), as well as 93 normal eyes from 93 participants.ExposuresLongitudinal spectral-domain optical coherence tomography (SD-OCT) volume scans (121 B-scans across 30° × 25°) were segmented with a deep-learning pipeline and standardized in a pointwise manner with age-adjusted normal data (z scores). Outer nuclear layer (ONL), photoreceptor inner segment (IS), and outer segment (OS) thickness were quantified along evenly spaced contour lines surrounding GA lesions. Linear mixed models were applied to assess the association between photoreceptor-related imaging features and GA progression rates and characterize the pattern of photoreceptor degeneration over time.Main outcomes and measuresAssociation of ONL thinning with follow-up time (after adjusting for age, retinal topography [z score], and distance to the GA boundary).ResultsThe study included 158 eyes of 89 patients (51 women and 38 men) with a mean (SD) age of 77.7 (7.1) years. The fully automated B-scan segmentation was accurate (dice coefficient, 0.82; 95% CI, 0.80-0.85; compared with manual markings) and revealed a marked interpatient variability in photoreceptor degeneration. The ellipsoid zone (EZ) loss-to-GA boundary distance and OS thickness were prognostic for future progression rates. Outer nuclear layer and IS thinning over time was significant even when adjusting for age and proximity to the GA boundary (estimates of -0.16 μm/y; 95% CI, -0.30 to -0.02; and -0.17 μm/y; 95% CI, -0.26 to -0.09).Conclusions and relevanceDistinct and progressive alterations of photoreceptor laminae (exceeding GA spatially) were detectable and quantifiable. The degree of photoreceptor degeneration outside of regions of retinal pigment epithelium atrophy varied markedly between eyes and was associated with future GA progression. Macula-wide photoreceptor laminae thinning represents a potential candidate end point to monitor treatment effects beyond mere GA lesion size progression.

Dataset Information

Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency.

Purpose

Methods

Results

Conclusions

Publications

Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency.

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