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MiRNA Changes in Retinal Ganglion Cells after Optic Nerve Crush and Glaucomatous Damage.

ABSTRACT: The purpose of this study was to characterize the miRNA profile of purified retinal ganglion cells (RGC) from healthy and diseased rat retina. Diseased retina includes those after a traumatic optic nerve crush (ONC), and after ocular hypertension/glaucoma. Rats were separated into four groups: healthy/intact, 7 days after laser-induced ocular hypertension, 2 days after traumatic ONC, and 7 days after ONC. RGC were purified from rat retina using microbeads conjugated to CD90.1/Thy1. RNA were sequenced using Next Generation Sequencing. Over 100 miRNA were identified that were significantly different in diseased retina compared to healthy retina. Considerable differences were seen in the miRNA expression of RGC 7 days after ONC, whereas after 2 days, few changes were seen. The miRNA profiles of RGC 7 days after ONC and 7 days after ocular hypertension were similar, but discrete miRNA differences were still seen. Candidate mRNA showing different levels of expression after retinal injury were manipulated in RGC cultures using mimics/AntagomiRs. Of the five candidate miRNA identified and subsequently tested for therapeutic efficacy, miR-194 inhibitor and miR-664-2 inhibitor elicited significant RGC neuroprotection, whereas miR-181a mimic and miR-181d-5p mimic elicited significant RGC neuritogenesis.

SUBMITTER: Mead B

PROVIDER: S-EPMC8305746 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Subtype-specific response of retinal ganglion cells to optic nerve crush.

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Retinal Ganglion Cell Loss is Delayed Following Optic Nerve Crush in NLRP3 Knockout Mice.

Project description:The NLRP3 inflammasome, a sensor for a variety of pathogen- and host-derived threats, consists of the adaptor ASC (Apoptosis-associated Speck-like protein containing a Caspase Activation and Recruitment Domain (CARD)), pro-caspase-1, and NLRP3 (NOD-Like Receptor family Pyrin domain containing 3). NLRP3-induced neuroinflammation is implicated in the pathogenesis and progression of eye diseases, but it remains unclear whether activation of NLRP3 inflammasome contributes to retinal ganglion cell (RGC) death. Here we examined NLRP3-induced neuroinflammation and RGC survival following partial optic nerve crush (pONC) injury. We showed that NLRP3 was up-regulated in retinal microglial cells following pONC, propagating from the injury site to the optic nerve head and finally the entire retina within one day. Activation of NLRP3-ASC inflammasome led to the up-regulation of caspase-1 and a proinflammatory cytokine, interleukin-1β (IL-1β). In NLRP3 knockout mice, up-regulation of ASC, caspase-1, and IL-1β were all reduced, and, importantly, RGC and axon loss was substantially delayed following pONC injury. The average survival time of RGCs in NLRP3 knockout mice was about one week longer than for control animals. Taken together, our study demonstrated that ablating the NLRP3 gene significantly reduced neuroinflammation and delayed RGC loss after optic nerve crush injury.

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Activating Transcription Factor 3 (ATF3) Protects Retinal Ganglion Cells and Promotes Functional Preservation After Optic Nerve Crush.

Project description:Purpose:To investigate the possible role of activating transcription factor 3 (ATF3) in retinal ganglion cell (RGC) neuroprotection and optic nerve regeneration after optic nerve crush (ONC). Methods:Overexpression of proteins of interest (ATF3, phosphatase and tensin homolog [PTEN], placental alkaline phosphatase, green fluorescent protein) in the retina was achieved by intravitreal injections of recombinant adenovirus-associated viruses (rAAVs) expressing corresponding proteins. The number of RGCs and αRGCs was evaluated by immunostaining retinal sections and whole-mount retinas with antibodies against RNA binding protein with multiple splicing (RBPMS) and osteopontin, respectively. Axonal regeneration was assessed via fluorophore-coupled cholera toxin subunit B labeling. RGC function was evaluated by recording positive scotopic threshold response. Results:The level of ATF3 is preferentially elevated in osteopontin+/RBPMS+ αRGCs following ONC. Overexpression of ATF3 by intravitreal injection of rAAV 2 weeks before ONC promoted RBPMS+ RGC survival and preserved RGC function as assessed by positive scotopic threshold response recordings 2 weeks after ONC. However, overexpression of ATF3 and simultaneous downregulation of PTEN, a negative regulator of the mTOR pathway, combined with ONC, only moderately promoted short distance RGC axon regeneration (200 μm from the lesion site) but did not provide additional RGC neuroprotection compared with PTEN downregulation alone. Conclusions:These results reveal a neuroprotective effect of ATF3 in the retina following injury and identify ATF3 as a promising agent for potential treatments of optic neuropathies.

| S-EPMC7326601 | biostudies-literature

Longitudinal profile of retinal ganglion cell damage after optic nerve crush with blue-light confocal scanning laser ophthalmoscopy.

Project description:To investigate the long-term longitudinal profile of retinal ganglion cell (RGC) damage after optic nerve crush with a new technique for in vivo imaging of RGCs.A blue-light confocal scanning laser ophthalmoscope (bCSLO; 460 nm excitation, 490 nm detection) was used to image Thy-1 CFP mice aged 6 to 9 months (n = 5) before optic nerve crush, weekly after crush for 3 weeks, and at weeks 10 and 50 after optic nerve crush. A sham procedure was performed in the contralateral eye, and it was imaged as a control. Corresponding retinal areas before and after optic nerve crush were compared, and the fluorescent spots were counted manually. The longitudinal profile of RGC degeneration was modeled and compared with one-phase and two-phase exponential decay equations.A significant and progressive loss of fluorescent spots was found after optic nerve crush with 18.6% +/- 2.3%, 11.3% +/- 3.4%, 8.8% +/- 5.3%, 4.2% +/- 3.1%, and 3.3% +/- 2.1% of Thy-1-expressing RGCs remaining at weeks 1, 2, 3, 10, and 50, respectively, after optic nerve crush (P < 0.001; n = 5). There was no change in the fluorescence density in the contralateral control (P = 0.893). Two-phase exponential decay (y = 0.03 + 0.83e(-)(2.78t) + 0.14e(-)(0.30t)) was a better fit than one-phase exponential decay (y = 0.94e(-)(1.93t) + 0.06; P = 0.003) equations, with half-lives of fast phase and slow phase of 1.7 days and 16.3 days, respectively.The longitudinal profile of RGC degeneration after optic nerve crush is characterized by a two-phase exponential decay model. bCSLO imaging provides an efficient and noninvasive approach to the longitudinal study of progressive RGC damage.

| S-EPMC5557086 | biostudies-other

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