Pseudoexfoliation syndrome (PXF), a systemic disease typified in the eye by fibrillary white flakes or pigmented deposits in the anterior chamber, is currently of particular interest because one of its associated intercellular signaling pathways — the Notch pathway — can be neuroprotective; but, when altered, it is linked to protein build-up such as in pseudoexfoliation glaucoma (PXG) or with the amyloid plaques of Alzheimer’s disease (AD).
In various tissues, Notch signaling helps manage cell growth, differentiation, and cell death. Prior studies have shown the Notch pathway to be necessary for lens development, ciliary body formation, and regulation of aqueous humor secretion — Notch molecules are also expressed in the trabecular meshwork. A team of researchers designed a prospective investigation to explore differing phenotypes in eyes with PXF, and impacts of Notch signaling between cells, now published in Journal of Glaucoma.
Notch pathway ligands, receptors, and target genes were assessed in tissues of anterior lens capsules sampled from the study eye of 106 patients who were at least 40 years of age during cataract surgery. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to profile Notch molecules in 47 lens capsules. Dot-blot assay affirmed qRT-PCR in evaluations of 37 lens samples, and immunostaining protein analysis yielded comparable results in 22 capsules. The observational investigation took place at a tertiary eye clinic from January 2016 to July 2018. Four groups comprised 27 patients with PXF, 24 participants with PXG, 22 individuals with primary open-angle glaucoma (POAG), and 33 control participants with cataract only.
Data yielded straightforward results for all 3 Notch molecules, including the mRNA level of NOTCH4 receptors in PXF tissue was more than 14 times greater than in control lens capsules (P <.001), and considerably higher than in PXG ( P =.003) and POAG tissue (P <.001). The mRNA and protein expression of Delta-like ligand 3 (DLL3) and DLL 4 were also significantly upregulated in capsules of eyes with PXF compared with controls (P <.05), and not upregulated in tissue of patients with PXG or POAG.
Eyes with both pseudoexfoliation deposits and glaucoma did not display a similar rise in Notch, and therefore “an increased Notch signaling may be protective against the development of secondary glaucoma,” the investigation explains. Expression of downstream target genes HES5, HES3, and HEY1 was also higher for patients with PXF compared with control individuals, the PXG and POAG cohorts.
Researchers speculate that upregulation of Notch creates a decrease in IOP, or produces a neuroprotective effect “at the level of the retinal ganglion cells.” Previous studies have demonstrated that reduced Notch signaling is linked to decreased neuroprotection of Muller cells, as well as findings indicating Notch is involved with survival of retinal ganglion cells. Thus, Notch may decrease reactive oxygen species, and increase expression of growth-associated genes such as GAP43 which is suspected to be protective for glaucoma.
A limitation of the current investigation is that it examined only ocular tissue from the anterior lens capsule. An unexpected finding was demonstrated by incorporating a POAG cohort that included eyes using IOP-lowering drops — Notch molecule expression did not significantly differ compared with the control group, and thus showed little impact of eyedrops on the study of Notch pathway.
Pradhan ZS, Dixit S, Krishna L, et al. Upregulated NOTCH signaling in the lens of patients with pseudoexfoliation syndrome compared to pseudoexfoliation glaucoma suggests protective role. J Glaucoma. Published online January 20, 2022. doi:10.1097/IJG.0000000000001975