Elucidating the Disease Mechanism Associated with Elastogenesis in Pseudoexfoliation Syndrome An In Vitro and Ex Vivo study

Abstract

Pseudoexfoliation syndrome (PXF) is an elastogenic disorder with accumulation of pseudoexfoliative material, containing ECM molecules, chiefly Elastin. The accumulation is seen on various ocular tissues, especially in the anterior segment tissues like lens capsule, Iris and Trabecular meshwork. However, the pathogenesis of the disease with respect to dysregulation of elastin synthesis and functional elastin is poorly understood. The study focussed on tissue-based and cell-based evaluation of the expression and regulation of elastin. Herein, for the first time the lens capsule tissue and aqH from PXF cases were compared to cataract-alone disease controls at the level of gene, protein expression on the key components of elastosis machinery. The study revealed increased elastogenesis in lens epithelial cells associated with PXF pathology and its progression to PXF-G. Further, mechanistic insights were obtained from Elastin interactome through dry and wet lab approaches that showed novel proteins and pathways associated with Elastin dysregulation in PXF. CONCLUSION: The study reveals in detail the elastosis mechanism associated with PXF seen in the lens capsule tissue apart from aqH of PXF cases compared to cataract-alone cases in terms of the upregulated proteins involved in the synthesis of mature elastin. The in vitro studies show that the PXF-associated pathogenic factors increase elastin expression in lens epithelium through ERK, p38 MAPK and JNK signalling pathways via Sp1 and c Jun transcription. These factors also promote upregulation of LOX and LOXL1 that crosslink elastin. The lens levels of Hcy are elevated in PXF and the Hcy metabolizing enzymes are down-regulated accounting for the elevated Hcy levels in PXF and PXF-G. Hcy alters secondary structure of elastin and leads to aggregation and amyloid formation of elastin. The elastin-interacting proteins deciphered via in silico studies possess similar biological functions to that of elastininteracting proteins obtained by elastin immunoprecipitation.